Amyloid-beta Proteins

Latest Research News

Lowering blood pressure prevents worsening brain damage in elderly

A clinical trial involving 199 hypertensive older adults (average age 81) found that those who took medicine to keep their 24-hour systolic blood pressure around 130 mm Hg for three years showed 40% less accumulation of white matter lesions compared with those taking medicine to maintain a systolic blood pressure around 145 mm Hg.

60% of the patients maintained their target blood pressure throughout the full three years, and data from these alone showed an even bigger difference in number of brain lesions.

The study used around-the-clock ambulatory blood pressure monitors, which measured participants' blood pressure during all activities of daily living.

Participants had an average systolic blood pressure around 150 mm Hg at the beginning of the trial.

The research was presented at the American College of Cardiology's 68th Annual Scientific Session.

https://www.eurekalert.org/pub_releases/2019-03/acoc-lbp031819.php

Brain lesions linked to higher blood pressure in older adults

A long-running study tracking 1,288 older adults (65+) until their deaths found that the risk and number of brain lesions increased with higher blood pressure. High blood pressure was also linked to increased risk of protein tangles in the brain.

Two-thirds of the subjects had high blood pressure, while about half had one or more brain infarcts. Those with an upper blood pressure of 147 had a 46% higher chance of having one or more lesions.

https://www.the-scientist.com/news-opinion/higher-blood-pressure-has-links-to-brain-lesions-in-older-adults-64495

Vascular risk interacts with amyloid levels to increase age-related cognitive decline

Data from 223 participants in the Harvard Aging Brain Study found that both elevated brain amyloid levels and higher vascular risk were associated with more rapid cognitive decline, with the most rapid changes seen in those with both factors. The interaction between the two factors appears to be synergistic rather than simply additive — that is, the interaction between vascular factors and amyloid burden produces more risk than would be predicted from simply adding the two together.

https://www.eurekalert.org/pub_releases/2018-05/mgh-vri052118.php

Arvanitakis, Z., Capuano, A. W., Lamar, M., Shah, R. C., Barnes, L. L., Bennett, D. A., & Schneider, J. A. (2018). Late-life blood pressure association with cerebrovascular and Alzheimer disease pathology. Neurology, 91(6), e517. https://doi.org/10.1212/WNL.0000000000005951

[4499] Rabin, J. S., Schultz A. P., Hedden T., Viswanathan A., Marshall G. A., Kilpatrick E., et al.
(2018).  Interactive Associations of Vascular Risk and β-Amyloid Burden With Cognitive Decline in Clinically Normal Elderly Individuals: Findings From the Harvard Aging Brain Study.
JAMA Neurology. 75(9), 1124 - 1131.

Although first reported in 1816, the fact that the brain is surrounded by lymphatic vessels, which connect the brain and the immune system, was only rediscovered in 2015.

Lymphatic vessels are part of the body's circulatory system. In most of the body they run alongside blood vessels. They transport lymph, a colorless fluid containing immune cells and waste, to the lymph nodes. Blood vessels deliver white blood cells to an organ and the lymphatic system removes the cells and recirculates them through the body. The process helps the immune system detect whether an organ is under attack from bacteria or viruses or has been injured.

Since then, brain scans have indicated that our brains drain some waste out through lymphatic vessels, and could act as a pipeline between the brain and the immune system.

More recent research suggests the vessels are vital to the brain's ability to cleanse itself. When a compound was used to improve the flow of waste from the brain to the lymph nodes in the neck of aged mice, their ability to learn and remember improved dramatically.

Moreover, obstructing the vessels in mice worsened the accumulation of harmful amyloid plaques in the brain.

https://www.eurekalert.org/pub_releases/2018-07/uovh-bdc072518.php

https://www.eurekalert.org/pub_releases/2017-10/nion-nru100317.php

[4498] Da Mesquita, S., Louveau A., Vaccari A., Smirnov I., R. Cornelison C., Kingsmore K. M., et al.
(2018).  Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease.
Nature. 560(7717), 185 - 191.

Absinta, Ha et al. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI, October 3, 2017, eLife: 10.7554/eLife.29738

A diet containing compounds found in green tea and carrots reversed Alzheimer's-like symptoms in mice genetically programmed to develop the disease. The two compounds were EGCG (epigallocatechin-3-gallate), a key ingredient in green tea, and FA (ferulic acid), which is found in carrots, tomatoes, rice, wheat and oats.

After three months, the treatment completely restored working memory deficits seen in the Alzheimer's mice. The compounds appeared to help prevent amyloid precursor proteins from breaking up into amyloid beta, as well as reduce neuroinflammation and oxidative stress in the brain.

The amount of EGCG and FA was no more than could be gained from an appropriate diet.

https://www.eurekalert.org/pub_releases/2019-03/uosc-asr030619.php

A mouse study has found that canola oil in the diet was associated with worsened memory, worsened learning ability, and weight gain in Alzheimer's mice.

Canola oil-treated animals also had greatly reduced levels of amyloid beta 1-40 (the “good” version), leading to more amyloid-beta plaques (made from amyloid beta 1-42), and a significant decrease in synapses.

The mice were given the equivalent of about two tablespoons of canola oil daily. The mice began their enriched diet at 6 months of age, before they developed any signs of Alzheimer's.

A previous study by the same researchers found that Alzheimer’s mice fed a diet enriched with extra-virgin olive oil had reduced levels of amyloid plaques and phosphorylated tau and experienced memory improvement.

Moreover, olive oil reduced inflammation in the brain, improved synaptic integrity, and dramatically increased levels of autophagy (the process by which waste products from cells are cleared away).

https://www.eurekalert.org/pub_releases/2017-12/tuhs-trc120617.php

https://www.eurekalert.org/pub_releases/2017-06/tuhs-tse061917.php

Periodontitis raises dementia risk

A 10-year South Korean study using data from 262,349 older adults (50+) has found that those with chronic periodontitis had a 6% higher risk for dementia than did people without periodontitis. This connection was true despite behaviors such as smoking, consuming alcohol, and remaining physically active.

https://www.eurekalert.org/pub_releases/2019-03/ags-pmr031519.php

Gum disease link to Alzheimer's explained

Gum disease has been linked to Alzheimer's as a risk factor, and now an animal study provides evidence that Porphyromonas gingivalis (Pg), the bacterium associated with chronic gum disease, colonizes the brain and increases production of amyloid beta.

Moreover, the bacterium's toxic enzymes (gingipains) have been found in the neurons of patients with Alzheimer’s. Gingipain levels were associated with two markers: tau, and ubiquitin (a protein tag that marks damaged proteins).

When molecule therapies targeting Pg gingipains were applied, there was reduced bacterial load of an established Pg brain infection, blocked amyloid-beta production, reduced neuroinflammation and protected neurons in the hippocampus.

Around half the population are said to have this bacteria in some form, and around 10% of those with the bacteria will develop serious gum disease, loose teeth, and have an increased risk of developing Alzheimer´s disease.

https://www.eurekalert.org/pub_releases/2019-01/uol-nsd012319.php

https://www.eurekalert.org/pub_releases/2019-06/tuob-byt060319.php

Mouse study links periodontal disease bacteria to greater amyloid plaques, brain inflammation, neuron death

A mouse study found that long-term exposure to periodontal disease bacteria resulted in significantly higher amounts of amyloid beta plaque, more brain inflammation and fewer intact neurons. It’s important to note that the mice used in the study were not genetically engineered to develop Alzheimer's.

https://www.eurekalert.org/pub_releases/2018-10/uoia-pdb100318.php

Data from the Harvard Aging Brain Study found that higher amyloid beta levels were associated with increasing anxiety symptoms in cognitively normal older adults. The results suggest that worsening anxious-depressive symptoms may be an early predictor of elevated amyloid beta levels.

The study involved 270 cognitively healthy older adults (62-90). For five years, participants were annually assessed for depression, apathy-anhedonia, dysphoria, and anxiety.

https://www.eurekalert.org/pub_releases/2018-01/bawh-aa011118.php

Donovan et al. 2017. Longitudinal Association of Amyloid Beta and Anxious-Depressive Symptoms in Cognitively Normal Older Adults. The American Journal of Psychiatry DOI: 10.1176/appi.ajp.2017.17040442

Aging linked to impaired garbage collection in the brain

A mouse study has shown that, as cells age, their ability to remove damaged proteins and structures declines.

The process of waste management, called autophagy, involves a component within the cell (an autophagosome) engulfing misfolded proteins or damaged structures (putting them in a garbage bag, essentially). The autophagosome then fuses with a second cellular structure, called a lysosome, that contains the enzymes needed to breakdown the garbage, allowing the components to be recycled and reused.

It’s thought that this decline in autophagy makes neurons more vulnerable to genetic or environmental risks.

The mouse study found that aging brought a significant decrease in the number of autophagosomes produced, along with pronounced defects in their structure.

However, activating the protein WIPI2B restored autophagosome formation.

https://www.eurekalert.org/pub_releases/2019-07/uops-tot071919.php

Breakdown in cleaning process in mitochondria linked to Alzheimer's

A cleaning process in brain cells called mitophagy breaks down defective mitochondria and reuses the proteins that they consist of. When the process breaks down, defective mitochondria accumulate in brain cells.

Research has now found that this is markedly present in cells from both humans and animals with Alzheimer's. Moreover, when active substances targeted at the cleaning process were tried in live animals, their Alzheimer's symptoms almost disappeared.

https://www.eurekalert.org/pub_releases/2019-02/uoct-oc021419.php

Microglia may spread toxic tau during early Alzheimer's

A 2015 study found how toxic tau fibrils spread during the early stages of Alzheimer's disease. Apparently the fibrils (accumulations of tau proteins) can be carried from one neuron to another by microglia.

Microglia act as the brain's immune cells, in which role they identify and clear damage and infection. They clear damage by first engulfing dead cells, debris, inactive synapses or even unhealthy neurons, then releasing nano-scale particles called exosomes, which can be absorbed by other cells.

It used to be thought that exosomes simply help the cell to get rid of waste products. It now appears that cells throughout the body use exosomes to transmit information. This requires them to contain both proteins and genetic material, which other cells can absorb. Hence their ability to spread tau protein, and hence, it now seems, their ability to also transport amyloid-beta.

http://www.eurekalert.org/pub_releases/2015-10/bumc-rdr100515.php

https://www.eurekalert.org/pub_releases/2018-06/lu-nmb061318.php

Microglia link Alzheimer’s amyloid and tau

Amyloid plaques and tau tangles are key biomarkers for Alzheimer’s, but research indicates that it is the tau tangles that are the real problem — the main problem with amyloid plaques is that they lead to tau tangles. A new study indicates how that happens.

A mouse study modified the TREM2 genes, which affect the health of microglia. So some mice carried the common variant of the gene, meaning that their microglia were fully functional, and some carried the risky variant, or no gene at all.

When seeded with tau protein from Alzheimer’s patients, those brains with weakened microglia produced more tau tangle-like structures near the amyloid plaques than in mice with functional microglia.

It was also revealed that microglia normally form a cap over amyloid plaques that limits their toxicity to nearby neurons. When the microglia failed to do that, neurons suffered more damage, creating an environment that fostered the formation of tau tangle-like lesions.

The findings were supported by the finding that humans with TREM2 mutations who died with Alzheimer’s had more tau tangle-like structures near their amyloid plaques than people who died with Alzheimer’s but didn’t have the risky gene.

https://www.futurity.org/alzheimers-disease-amyloid-plaques-tau-2095692/

https://www.eurekalert.org/pub_releases/2019-06/wuso-aml062319.php

However, it should be noted that in more advanced stages of Alzheimer’s, mice with the common TREM2 variant showed faster plaque growth. This appears to be linked to the gene inducing microglia to produce ApoE, which enhances aggregate formation.

The finding adds to evidence that Alzheimer's treatment has to take into account the stage at which the disease is at.

https://www.eurekalert.org/pub_releases/2019-01/d-gc-dic010819.php

Another study that modified the TREM2 gene in mice found that the difference between those with the gene and those without was not in the amount of tau tangles, but rather in the way their immune cells responded to the tau tangles. The microglia in mice with TREM2 were active, releasing compounds that in some circumstances help fight disease, but in this case primarily injured and killed nearby neurons. The microglia in mice without TREM2 were much less active, and their neurons were relatively spared.

https://www.eurekalert.org/pub_releases/2017-10/wuso-agp100617.php

http://www.futurity.org/trem2-alzheimers-disease-1573272/

Overactive microglia have multiple effects

A study found that, if the gene for the TDP-43 protein was turned off in microglia, its activity increased, and amyloid-beta was removed very efficiently. However, when TDP-43 was switched off in microglia in mice, it didn’t just get better at removing amyloid-beta, but also led to a significant loss of synapses.

Clearly, dysfunction of microglia is a complicated business, and it’s suggested that such dysfunction may be one reason why many Alzheimer's medications reduce amyloid plaques but fail to improve cognition.

https://www.eurekalert.org/pub_releases/2017-06/uoz-osc062917.php

Classifying brain microglia

Microglia come in many forms. A survey of brain microglia has classified microglia into at least nine distinct groups, including some types never detected in the past. Some types appeared almost exclusively in the embryonic or newborn stages, others only after injury.

One group tended to cluster near the brain's developing white matter. Another appears to be very inflammatory compared with other microglia, and has been found in people with MS.

Microglia were most diverse early in brain development, in the aged brain and in disease.

https://www.eurekalert.org/pub_releases/2018-12/bch-cbm120518.php

[4447] Stavoe, A. K. H., Gopal P. P., Gubas A., Tooze S. A., & Holzbaur E. L. F.
(2019).  Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons.
(Dikic, I., Marder E., & Hurley J. H., Ed.).eLife. 8, e44219.

[4448] Fang, E. F., Hou Y., Palikaras K., Adriaanse B. A., Kerr J. S., Yang B., et al.
(2019).  Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease.
Nature Neuroscience. 22(3), 401 - 412.

Maitrayee Sardar Sinha, Anna Ansell-Schultz, Livia Civitelli, Camilla Hildesjö, Max Larsson, Lars Lannfelt, Martin Ingelsson and Martin Hallbeck, Alzheimer disease pathology propagation by exosomes containing toxic amyloid-beta oligomers, Acta Neuropathologica, published online 13 June 2018, doi: 10.1007/s00401-018-1868-1 https://link.springer.com/article/10.1007/s00401-018-1868-1

[4451] Leyns, C. E. G., Gratuze M., Narasimhan S., Jain N., Koscal L. J., Jiang H., et al.
(2019).  TREM2 function impedes tau seeding in neuritic plaques.
Nature Neuroscience. 22(8), 1217 - 1222.

Parhizkar et al. (2019): "Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE", Nature Neuroscience, DOI: 10.1038/s41593-018-0296-9

Leyns C, Ulrich J, Finn M, Stewart F, Koscal L, Remolina Serrano J, Robinson G, Anderson E, Colonna M, Holtzman DM. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proceedings of the National Academy of Sciences. Week of Oct. 9, 2017.

[4452] Paolicelli, R. C., Jawaid A., Henstridge C. M., Valeri A., Merlini M., Robinson J. L., et al.
(2017).  TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss.
Neuron. 95(2), 297 - 308.e6.

[4464] Hammond, T. R., Dufort C., Dissing-Olesen L., Giera S., Young A., Wysoker A., et al.
(2019).  Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes.
Immunity. 50(1), 253 - 271.e6.

Data from 1,215 older adults, of whom 173 (14%) were African-American, has found that, although brain scans showed no significant differences between black and white participants, cerebrospinal fluid (CSF) showed significantly lower levels of the brain protein tau in African-Americans.

While both groups showed the same (expected) pattern of higher tau levels being associated with greater chance of cognitive impairment, the absolute amounts of tau protein were consistently lower in African-Americans.

However, when APOE status was taken into account, it was found that those who held the low-risk variants of the “Alzheimer’s gene” had similar levels of tau, regardless of race. It was only African-Americans with the APOE4 gene variant that showed lower levels of tau.

This suggests that the APOE4 risk factor has different effects in African-Americans compared to non-Hispanic white Americans, and points to the need for more investigation into how Alzheimer’s develops in various populations.

Interestingly, another study, using data from 1798 patients (of whom 1690 were white), found that there was a strong gender difference in the association between APOE status and tau levels in the CSF.

Previous research has shown that the link between APOE4 and Alzheimer's is stronger in women than men. This study points to a connection with tau levels, as there was no gender difference in the association between APOE and amyloid-beta levels, amyloid plaques, or tau tangles.

https://www.futurity.org/alzheimers-disease-black-patients-1951502/

Morris JC, Schindler SE, McCue LM, et al. Assessment of Racial Disparities in Biomarkers for Alzheimer Disease. JAMA Neurol. Published online January 07, 2019. doi:10.1001/jamaneurol.2018.4249

Hohman TJ, Dumitrescu L, Barnes LL, et al. Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau. JAMA Neurol. 2018;75(8):989–998. doi:10.1001/jamaneurol.2018.0821

 

A study involving both mice and human cells adds to evidence that stress is a risk factor for Alzheimer's.

The study found that mice who were subjected to acute stress had more amyloid-beta protein in their brains than a control group. Moreover, they had more of a specific form of the protein, one that has a particularly pernicious role in the development of Alzheimer's disease.

When human neurons were treated with the stress hormone corticotrophin releasing factor (CRF), there was also a significant increase in the amyloid proteins.

It appears that CRF causes the enzyme gamma secretase to increase its activity. This produces more amyloid-beta.

The finding supports the idea that reducing stress is one part of reducing your risk of developing Alzheimer's.

A neurotic personality increases the risk of Alzheimer's disease

An interesting study last year supports this.

The study, involving 800 women who were followed up some 40 years after taking a personality test, found that women who scored highly in "neuroticism" in middle age, have a greater chance of later developing Alzheimer's. People who have a tendency to neuroticism are more readily worried, distressed, and experience mood swings. They often have difficulty in managing stress.

The women, aged 38 to 54, were first tested in 1968, with subsequent examinations in 1974, 1980, 1992, 2000, and 2005. Neuroticism and extraversion were assessed in 1968 using the Eysenck Personality Inventory. The women were asked whether they had experienced long periods of high stress at each follow-up.

Over the 38 years, 153 developed dementia (19%), of whom 104 were diagnosed with Alzheimer's (13% of total; 68% of those with dementia).

A greater degree of neuroticism in midlife was associated with a higher risk of Alzheimer's and long-standing stress. This distress accounted for a lot of the link between neuroticism and Alzheimer's.

Extraversion, while associated with less chronic stress, didn't affect Alzheimer's risk. However, high neuroticism/low extraversion (shy women who are easily worried) was associated with the highest risk of Alzheimer's.

The finding supports the idea that long periods of stress increase the risk of Alzheimer's, and points to people with neurotic tendencies, who are more sensitive to stress, as being particularly vulnerable.

http://www.eurekalert.org/pub_releases/2015-09/uof-uhr091615.php

http://www.eurekalert.org/pub_releases/2014-10/uog-anp101414.php

A study involving older adults has found that diabetes was associated with higher levels of tau protein and greater brain atrophy.

The study involved 816 older adults (average age 74), of whom 397 had mild cognitive impairment, 191 had Alzheimer's disease, and 228 people had no cognitive problems. Fifteen percent (124) had diabetes.

Those with diabetes had greater levels of tau protein in the spinal and brain fluid regardless of cognitive status. Tau tangles are characteristic of Alzheimer's.

Those with diabetes also had cortical tissue that was an average of 0.03 millimeter less than those who didn't have diabetes, regardless of their cognitive status. This greater brain atrophy in the frontal and parietal cortices may be partly related to the increase in tau protein.

There was no link between diabetes and amyloid-beta, the other main pathological characteristic of Alzheimer's.

Previous research has indicated that people with type 2 diabetes have double the risk of developing dementia. Previous research has also found that those who had been diabetic for longer had a greater degree of brain atrophy

The findings support the idea that type 2 diabetes may have a negative effect on cognition independent of dementia, and that this effect may be driven by an increase in tau phosphorylation.

http://www.eurekalert.org/pub_releases/2015-09/aaon-dab082715.php

An examination of the brains of three groups of deceased individuals (13 cognitively normal, aged 20-66; 16 non-demented older adults, aged 70-99; 21 individuals with Alzheimer's, aged 60-95) has found that amyloid starts to accumulate and clump inside basal forebrain cholinergic neurons in young adulthood. Other neurons didn't show the same extent of amyloid accumulation. Basal forebrain cholinergic neurons are the first to be affected, and to die, in aging and Alzheimer's.

http://www.eurekalert.org/pub_releases/2015-03/nu-aac022515.php

Analysis of brain scans and cognitive scores of 64 older adults from the NIA's Baltimore Longitudinal Study of Aging (average age 76) has found that, between the most cognitively stable and the most declining (over a 12-year period), there was no significant difference in the total amount of amyloid in the brain, but there was a significant difference in the location of amyloid accumulation. The stable group showed relatively early accumulation in the frontal lobes, while the declining group showed it in the temporal lobes.

http://www.eurekalert.org/pub_releases/2013-07/uops-pop071513.php

[3624] Yotter, R. A., Doshi J., Clark V., Sojkova J., Zhou Y., Wong D. F., et al.
(2013).  Memory decline shows stronger associations with estimated spatial patterns of amyloid deposition progression than total amyloid burden.
Neurobiology of Aging. 34(12), 2835 - 2842.

Analysis of 40 spinal marrow samples, 20 of which belonged to Alzheimer’s patients, has identified six proteins in spinal fluid that can be used as markers for Alzheimer's. The analysis focused on 35 proteins that are associated with the lysosomal network — involved in cleaning and recycling beta amyloid. None of the six proteins had previously been linked to Alzheimer’s.

http://www.eurekalert.org/pub_releases/2013-10/lu-ast102313.php

[3551] Armstrong, A., Mattsson N., Appelqvist H., Janefjord C., Sandin L., Agholme L., et al.
(2014).  Lysosomal Network Proteins as Potential Novel CSF Biomarkers for Alzheimer’s Disease.
NeuroMolecular Medicine. 16(1), 150 - 160.

New research supports the classification system for preclinical Alzheimer’s proposed two years ago. The classification system divides preclinical Alzheimer's into three stages:

Stage 1: Levels of amyloid beta begin to decrease in the spinal fluid. This indicates that the substance is beginning to form plaques in the brain.

Stage 2: Levels of tau protein start to increase in the spinal fluid, indicating that brain cells are beginning to die. Amyloid beta levels are still abnormal and may continue to fall.

Stage 3: In the presence of abnormal amyloid and tau biomarker levels, subtle cognitive changes can be detected by neuropsychological testing.

Long-term evaluation of 311 cognitively healthy older adults (65+) found 31% with preclinical Alzheimer’s, of whom 15% were at stage 1, 12% at stage 2, and 4% at stage 3. This is consistent with autopsy studies, which have shown that around 30% of cognitively normal older adults die with some preclinical Alzheimer's pathology in their brain. Additionally, 23% were diagnosed with suspected non-Alzheimer pathophysiology (SNAP), 41% as cognitively normal, and 5% as unclassified.

Five years later, 2% of the cognitively normal, 5% of those with SNAP, 11% of the stage 1 group, 26% of the stage 2 group, and 56% of the stage 3 group had been diagnosed with symptomatic Alzheimer's.

http://www.eurekalert.org/pub_releases/2013-09/wuso-apt092313.php

[3614] Vos, S JB., Xiong C., Visser P J., Jasielec M. S., Hassenstab J., Grant E. A., et al.
(2013).  Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study.
The Lancet Neurology. 12(10), 957 - 965.

Initial findings from an analysis of cerebrospinal fluid taken between 1995 and 2005 from 265 middle-aged healthy volunteers, of whom 75% had a close family member with Alzheimer’s disease, has found that the ratios of phosphorylated tau and amyloid-beta could predict mild cognitive impairment more than five years before symptom onset — the more tau and less amyloid-beta, the more likely MCI will develop. The rate of change in the ratio over time was also predictive — the more rapidly the ratio of tau to amyloid-beta went up, the more likely the eventual development of MCI.

The drop in amyloid-beta is thought to be because it is getting trapped in the plaques characteristic of Alzheimer’s.

http://www.futurity.org/spinal-fluid-test-may-predict-alzheimers/

[3592] Moghekar, A., Li S., Lu Y., Li M., Wang M-C., Albert M., et al.
(2013).  CSF biomarker changes precede symptom onset of mild cognitive impairment.
Neurology.

Studies linking head trauma with increased risk and earlier age of onset for Alzheimer's disease have yielded contradictory results. Now a population-based study involving 448 healthy older adults (70+) and 141 seniors with mild cognitive impairment has found that a history of head trauma was associated with higher levels of amyloid-beta plaques (a marker for Alzheimer’s) in those with MCI, but not in the cognitively normal. Similar rates of self-reported head trauma were found in the two groups (17% and 18%, respectively).

http://www.eurekalert.org/pub_releases/2013-12/aaon-acr122013.php

[3591] Mielke, M. M., Savica R., Wiste H. J., Weigand S. D., Vemuri P., Knopman D. S., et al.
(2014).  Head trauma and in vivo measures of amyloid and neurodegeneration in a population-based study.
Neurology. 82(1), 70 - 76.

A three-year study involving 152 adults aged 50 and older, of whom 52 had been recently diagnosed with mild cognitive impairment and 31 were diagnosed with Alzheimer's disease, has found that those with mild or no cognitive impairment who initially had amyloid-beta plaques showed greater cognitive decline than those whose brain scans were negative for plaques. Moreover, 35% of plaque-positive participants who started with MCI progressed to Alzheimer's, compared to 10% without plaque, and they were more than twice as likely to be started on cognitive-enhancing medication.

The fact that 90% of those with MCI but no plaque didn’t progress to Alzheimer's (within the three-year period) points to the value of using PET imaging to identify patients unlikely to decline, who can be reassured accordingly. The finding also points to the importance of plaque buildup in cognitive decline.

http://www.eurekalert.org/pub_releases/2014-03/dumc-pdi030514.php

[3569] Doraiswamy, M. P., Sperling R. A., Johnson K., Reiman E. M., Wong T. Z., Sabbagh M. N., et al.
(2014).  Florbetapir F 18 amyloid PET and 36-month cognitive decline:a prospective multicenter study.
Molecular Psychiatry.

A multi-year study involving 207 healthy older adults, in which their spinal fluids were repeatedly sampled and their brains repeatedly scanned, has found that disruptions in the default mode network emerges about the same time as chemical markers of Alzheimer’s appear in the spinal fluid (decreased amyloid-beta and increased tau protein). The finding suggests not only that amyloid-beta and tau pathology affect default mode network integrity early on, but that scans of brain networks may be an equally effective and less invasive way to detect early disease.

The greatest decrease in functional connectivity was found between the posterior cingulate and medial temporal regions. This decrease was not attributable to age or structural atrophy in these regions.

http://www.eurekalert.org/pub_releases/2013-08/wuso-bnd081913.php

[3617] Wang, L., Brier M. R., Snyder A. Z., & et al
(2013).  Cerebrospinal fluid aβ42, phosphorylated tau181, and resting-state functional connectivity.
JAMA Neurology. 70(10), 1242 - 1248.

The first detailed characterization of the molecular structures of amyloid-beta fibrils that develop in the brains of those with Alzheimer's disease suggests that different molecular structures of amyloid-beta fibrils may distinguish the brains of Alzheimer's patients with different clinical histories and degrees of brain damage. A comparison of amyloid-beta fibril fragments from the brain tissue of two patients with different clinical histories and degrees of brain damage found different molecular structures, confirming cell research showing that amyloid-beta fibrils grown in a dish have different molecular structures depending on the specific growth conditions.

Obviously, this is a very small study, and will need to be confirmed across more patients. However, it’s important for indicating that structural variations may correlate with variations in Alzheimer’s, and that structure-specific amyloid imaging agents may need to be used.

http://www.eurekalert.org/pub_releases/2013-09/cp-aps090513.php

[3587] Lu, J-X., Qiang W., Yau W-M., Schwieters C D., Meredith S C., & Tycko R.
(2013).  Molecular Structure of β-Amyloid Fibrils in Alzheimer’s Disease Brain Tissue.
Cell. 154(6), 1257 - 1268.

A new study involving 96 older adults initially free of dementia at the time of enrollment, of whom 12 subsequently developed mild Alzheimer’s, has clarified three fundamental issues about Alzheimer's: where it starts, why it starts there, and how it spreads.

Specifically, it begins in the lateral entorhinal cortex (LEC), a gateway to the hippocampus. Over time, Alzheimer's spreads from the LEC directly to other areas of the cerebral cortex, in particular the parietal cortex. It’s thought that it spreads by compromising the function of neurons in the LEC, which then compromises the integrity of neurons in adjoining areas.

Mouse models comparing the effects of elevated levels of tau in the LEC with elevated levels of APP, and with elevated levels of both, found that LEC dysfunction occurred only in the mice with high levels of both tau and APP. The LEC normally accumulates tau, making it more vulnerable to the accumulation of APP.

http://www.eurekalert.org/pub_releases/2013-12/cumc-ssw121713.php

[3582] Khan, U. A., Liu L., Provenzano F. A., Berman D. E., Profaci C. P., Sloan R., et al.
(2014).  Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease.
Nature Neuroscience. 17(2), 304 - 311.

Following on from the evidence that Alzheimer’s brains show higher levels of metals such as iron, copper, and zinc, a mouse study has found that amyloid plaques in Alzheimer’s-like brains with significant neurodegeneration have about 25% more copper than those with little neurodegeneration. This is consistent with a human study showing very high levels of copper in Alzheimer’s plaques.

Iron, though doubled in Alzheimer’s brains compared to controls, was not significantly different as a function of neurodegeneration, and zinc showed very little difference.

The findings suggest that the cellular control of copper is altered in some way in Alzheimer’s brains, while the increase in oxidized iron suggests it might be useful as a biomarker for the early diagnosis of Alzheimer’s.

http://www.eurekalert.org/pub_releases/2013-08/ip-elo082113.php

[3555] Bourassa, M. W., Leskovjan A. C., Tappero R. V., Farquhar E. R., Colton C. A., Van Nostrand W. E., et al.
(2013).  Elevated copper in the amyloid plaques and iron in the cortex are observed in mouse models of Alzheimer's disease that exhibit neurodegeneration.
Biomedical Spectroscopy and Imaging. 2(2), 129 - 139.

Data from 70 older adults (average age 76) in the Baltimore Longitudinal Study of Aging has found that those who reported poorer sleep (shorter sleep duration and lower sleep quality) showed a greater buildup of amyloid-beta plaques.

http://www.eurekalert.org/pub_releases/2013-10/tjnj-lsa101813.php

[3606] Spira, A. P., Gamaldo A. A., An Y., & et al
(2013).  Self-reported sleep and β-amyloid deposition in community-dwelling older adults.
JAMA Neurology. 70(12), 1537 - 1543.

A new function has been found for the amyloid precursor protein (APP), which may help explain how it goes awry in Alzheimer's disease. It appears that APP (which is involved in the creation of amyloid-beta), also helps control the growth and maturation of newborn brain cells, by regulating a specific microRNA (microRNA-574-5p) that normally promotes neurogenesis.

http://www.eurekalert.org/pub_releases/2014-04/s-nrd041814.php

[3626] Zhang, W., Thevapriya S., Kim P. J., Yu W-P., Shawn Je H., King Tan E., et al.
(2014).  Amyloid precursor protein regulates neurogenesis by antagonizing miR-574-5p in the developing cerebral cortex.
Nature Communications. 5,

New research helps explain the role of amyloid-beta plaques in the development of Alzheimer's, by finding that the prion protein known to bind strongly to small aggregates of amyloid-beta peptides, also attaches to large fibrillar clumps of amyloid-beta. However, it doesn’t break them down into smaller, more harmful pieces, as has been suggested. This suggests that prion-protein-based compounds might be a useful means of treatment, to stop these smaller pieces from forming.

http://www.eurekalert.org/pub_releases/2014-04/acs-tut042314.php

[3595] Nieznanski, K., Surewicz K., Chen S., Nieznanska H., & Surewicz W. K.
(2014).  Interaction between Prion Protein and Aβ Amyloid Fibrils Revisited.
ACS Chemical Neuroscience. 5(5), 340 - 345.

Creating amyloid-beta requires the convergence of a protein called amyloid precursor protein (APP) and an enzyme that cleaves APP into smaller toxic fragments (beta-secretase or BACE). Both APP and BACE are common in the brain, so why don’t we all get Alzheimer’s?

Cultured hippocampal neurons and tissue from human and mouse brains have now revealed that healthy brain cells largely segregate APP and BACE-1 into distinct compartments as soon as they are manufactured, ensuring the two proteins don’t have much contact with each other. However, in conditions promoting greater production of amyloid-beta protein (an increase in neuronal electrical activity), the convergence of APP and BACE also increases.

The findings not only add to our understanding of how Alzheimer’s gets started, but also suggests a possible therapeutic target: molecules that can physically keep APP and BACE-1 apart.

http://www.eurekalert.org/pub_releases/2013-08/uoc--wdw080213.php

http://www.alzforum.org/news/research-news/neural-activity-tips-endosomal-balance-hastens-amyloid-pathology

[3566] Das, U., Scott D. A., Ganguly A., Koo E. H., Tang Y., & Roy S.
(2013).  Activity-Induced Convergence of APP and BACE-1 in Acidic Microdomains via an Endocytosis-Dependent Pathway.
Neuron. 79(3), 447 - 460.

A study involving 74 older adults (70+), of whom 3 had mild dementia, 33 were cognitively normal and 38 had mild cognitive impairment, has found that high levels of "good" cholesterol and low levels of "bad" cholesterol correlated with lower levels of the amyloid-beta plaques in the brain (a hallmark of Alzheimer's disease).

http://www.eurekalert.org/pub_releases/2013-12/uoc--hga122613.php

Last year, a cancer drug, Bexarotene, was touted as a potential treatment for Alzheimer’s disease. However, four independent studies have now failed to replicate the most dramatic result of the original study: a claim that the drug could clear half the amyloid plaques in a mere 72 hours.

Still, two of the studies confirmed findings that the drug reduced levels of amyloid-beta, and one showed improved cognition in mice.

The inconsistencies suggest more research is needed. The drug is now being tested in humans.

http://www.nature.com/news/studies-cast-doubt-on-cancer-drug-as-alzheimer-s-treatment-1.13058

[3435] Shen, H.
(2013).  Studies cast doubt on cancer drug as Alzheimer's treatment.
Nature.

We know that the E4 variant of the APOE gene greatly increases the risk of developing Alzheimer’s disease, but the reason is a little more mysterious. It has been thought that it makes it easier for amyloid plaques to form because it produces a protein that binds to amyloid beta. However, a new study shows that APOE and amyloid beta don’t bind together in cerebrospinal fluid and in fluids present outside cells grown in dishes, making it unlikely that they are binding together in the brain.

Mouse and cell culture experiments suggest instead that the APOE protein may be blocking a pathway that normally helps degrade amyloid beta — both APOE and amyloid beta seem to compete to bind to an astrocyte receptor. Previous work has shown that astrocytes can degrade amyloid beta.

The findings suggest that therapeutic strategies that target APOE need to be redirected.

http://www.futurity.org/health-medicine/sticky-questions-about-role-of-alzheimer%e2%80%99s-gene/

[3410] Verghese, P. B., Castellano J. M., Garai K., Wang Y., Jiang H., Shah A., et al.
(2013).  ApoE influences amyloid-β (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions.
Proceedings of the National Academy of Sciences. 110(19), E1807 - E1816.

A theory that changes in fat metabolism in the membranes of nerve cells play a role in Alzheimer's has been supported in a recent study. The study found significantly higher levels of ceramide and cholesterol in the middle frontal gyrus of Alzheimer's patients. The researchers suggest that alterations in fats (especially cholesterol and ceramide) may contribute to a "neurodegenerative cascade" that destroys neurons in Alzheimer's, and that the accumulation of ceramide and cholesterol is triggered by the oxidative stress brought on by the presence of the toxic beta amyloid peptide. The study also suggests a reason for why antioxidants such as vitamin E might delay the onset of Alzheimer's: treatment with Vitamin E reduced the levels of ceramide and cholesterol, resulting in "a significant decrease in the number of neurons killed by the beta amyloid and oxidative stress.

Cutler, R.G., Kelly, J., Storie, K., Pedersen, W.A., Tammara, A., Hatanpaa, K., Troncoso, J.C. & Mattson, M.P. 2004. Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease. PNAS, 101, 2070-5.

Older news items (pre-2010) brought over from the old website

Why and how plaques form

Progress toward a drug that could actually stop Alzheimer’s

Amyloid plaques, characteristic of Alzheimer’s, are created when the amyloid precursor protein is cut into pieces incorrectly, which is governed by the γ-secretase complex. Acting on this complex is problematic however, as it is also involved in the regulation of a number of other essential proteins. New research with mouse models has now found that the complex assumes a different shape and function according to the tissue in which the secretase is active, and that they can specifically target the relevant variant, Aph1B γ-secretase, thus reducing formation of the plaques without any harmful side effects. The finding raises hopes for a drug that, for the first time, will succeed in stopping or even preventing Alzheimer's disease. However, many years of further research and development will be needed before such a drug will reach marketable status.

Serneels, L. et al. 2009. γ-Secretase Heterogeneity in the Aph1 Subunit: Relevance for Alzheimer's Disease. Science, Published Online March 19.

http://www.eurekalert.org/pub_releases/2009-03/vfi-pta031909.php

Paradoxical finding may shed new light on memory loss

Following a previous study, in which genetically engineered mice were prevented from getting Alzheimer’s by blocking a single site of cleavage of amyloid precursor protein (APP), studies of brain tissue from Alzheimer’s patients were found to have clearly more of this cleavage process than people of the same age who do not have the disease. However, much younger people without Alzheimer’s displayed as much as ten times the amount of the same cleavage event. The researchers now believe that normal memory loss is hyper-activated in Alzheimer’s, pointing to Alzheimer’s as a disorder affecting the plasticity, the ability to make and break memories, of the brain. Rather than the problem lying with the buildup of A-beta, the researchers suggest the problem lies in the downstream signaling of A-beta.

Banwait, S. et al. 2008. C-terminal cleavage of the amyloid-ß protein precursor at Asp664: a switch associated with Alzheimer's disease. Journal of Alzheimer’s Disease, 13 (1), 1-16.

http://www.eurekalert.org/pub_releases/2008-03/ip-paf031208.php

Progression of Alzheimer's disease revealed

A new imaging agent is giving researchers information never before available about how and where Alzheimer’s progresses in the brain. Results suggest that amyloid plaques deposit sequentially, first appearing in the cingulate cortex/precuneus and frontal cortex areas, then progressing to the parietal and temporal cortex and caudate, and finally reaching the occipital cortex and sensory-motor cortex. These findings may explain why memory and judgment are often the brain functions first affected in Alzheimer's disease.

Klunk & Mathis 2005. Can In Vivo Amyloid Imaging with Pittsburgh Compound-B Tell Us Anything About the Time Course of Amyloid Deposition in Alzheimer's Disease. Paper presented at the 35th Annual Meeting of the Society for Neuroscience, Nov. 12-16, in Washington, D.C.

http://www.eurekalert.org/pub_releases/2005-11/uopm-ctt111105.php

New light on how amyloid beta accumulation leads to long-term memory loss

A study using genetically engineered mice has shed new light on why the damage to brain tissue seen in Alzheimer’s leads to the loss of long-term memories. It seems that the accumulation of amyloid-beta peptides can deplete key proteins in the hippocampus, and this process can be worsened by increased activity of an enzyme called Fyn. The conversion of new information into long-term memories requires proteins (such as Arc and Fos) that help strengthen the synapses between specialized neurons in the hippocampus. Fyn is located at the synapses, where it regulates the activity of several memory-related proteins; increases in Fyn activity significantly increase the susceptibility of the hippocampal granule cells to the amyloid beta-induced depletion of memory proteins.

Palop, J.J., Chin, J., Bien-Ly, N., Massaro, C., Yeung, B.Z., Yu, G-Q. & Mucke, L. 2005. Vulnerability of Dentate Granule Cells to Disruption of Arc Expression in Human Amyloid Precursor Protein Transgenic Mice. Journal of Neuroscience, 25, 9686-9693.

Chin, J., Palop, J.J., Puoliväli, J., Massaro, C., Bien-Ly, N., Gerstein, H., Scearce-Levie, K., Masliah, E. & Mucke, L. 2005. Fyn Kinase Induces Synaptic and Cognitive Impairments in a Transgenic Mouse Model of Alzheimer's Disease. Journal of Neuroscience, 25, 9694-9703.

http://www.eurekalert.org/pub_releases/2005-10/gi-szi101705.php

New light on why plaques form

Alzheimer's disease is characterized by an increasing deposit of the amyloid-β protein in the brain, which collect to form aggregations called 'plaques'. New research has unraveled how certain plaques are formed. It seems the plaques attach primarily to blood vessels, which show clear structural damage, leading to leakage between the blood vessels and the brain. Under normal circumstances, the blood vessels transport excess amyloid-β protein away from the brain. The findings suggest new treatment approaches.

Kumar-Singh, S., Pirici, D., McGowan, E., Serneels, S., Ceuterick, C., Hardy, J., Duff, K., Dickson, D. & Van Broeckhoven, C. 2005. Dense-Core Plaques in Tg2576 and PSAPP Mouse Models of Alzheimer’s Disease Are Centered on Vessel Walls. American Journal of Pathology, 167, 527-543.

http://www.eurekalert.org/pub_releases/2005-07/vfii-adn072705.php

Finding an Alzheimer's switch

One prominent theory of the cause of Alzheimer's involves the so-called "amyloid beta protein cascade," in which a protein called APP is clipped into shorter pieces by enzymes known as secretases. If the portion of APP clipped by the beta form of secretase is further clipped by a third form, gamma secretase, the resulting fragments are amyloid beta peptides, A-beta 40 and A-beta 42. A-beta 42 in particular is toxic and causes the formation of amyloid plaques. A new study has uncovered an unsuspected subunit of gamma-secretase, the protein CD147, which apparently regulates the production of the toxic peptides that cause amyloid plaques. CD147 is expressed in many tissues and has many functions besides its role in tumor invasion, including reproduction, inflammation, and protein transport and sorting within cells. It also has a role in neural function: when the CD147 gene is deleted in mice, the result is defective nervous system development, loss of working memory, spatial learning deficits, and disorientation — behaviors remarkably suggestive of Alzheimer's disease. Future research will attempt to uncover exactly how CD147 prevents excessive production of A-beta 42 peptides, and what causes it to fail.

Zhou, S., Zhou, H., Walian, P.J. & Jap, B.K. 2005. CD147 is a regulatory subunit of the ã-secretase complex in Alzheimer's disease amyloid â-peptide production. Proceedings of the National Academy of Sciences, Published online before print May 12, 2005, 10.1073/pnas.0502768102.

http://www.eurekalert.org/pub_releases/2005-05/dbnl-faa051305.php

Beta amyloid accumulation shown to be trigger for onset of Alzheimer's

A study using genetically engineered mice has determined that early beta amyloid accumulation within neurons is the trigger for the onset of memory decline in Alzheimer's. The study found that decline in long-term memory retention began with the buildup of beta amyloid in neurons of the hippocampus, amygdala and cerebral cortex regions of the mice's brains, although the plaques and tangles characteristic of Alzheimer’s had not yet developed. When the beta amyloid was cleared away, the memory impairments disappeared; the reemergence of beta amyloid inside the neurons marked again the onset of memory problems.

Billings, L.M., Oddo, S., Green, K.N., McGaugh, J.L. & LaFerla, F.M. 2005. Intraneuronal Aβ Causes the Onset of Early Alzheimer’s Disease-Related Cognitive Deficits in Transgenic Mice. Neuron, 45(5), 675-688.

http://www.eurekalert.org/pub_releases/2005-03/uoc--uri030105.php

Progress toward a more targeted treatment of Alzheimer's disease

A major role in the process by which plaques develop is played by γ-secretase, an enzyme that cuts proteins in a particular place. Sometimes the γ-secretase cleavage goes wrong, causing the creation of a by-product that sticks together and precipitates (plaques). Although γ-secretase is divided into several entities, it’s been assumed that the complex acts as a homogeneous unit. However, new research has found that γ-secretase's various sub-units exhibit very diverse, tissue-specific activity. The findings should make it possible to develop medicines that are targeted on a single sub-unit and thereby have a much more specific action, with fewer unwanted side-effects.

Serneels, L. et al. 2005. Differential contribution of the three Aph1 genes to g-secretase activity in vivo. Proceedings of the National Academy of Sciences, 102, 1719-1724; published online before print January 21 2005

http://www.eurekalert.org/pub_releases/2005-02/vfii-pta013105.php

Certain antibodies might clear amyloid-beta proteins from brain

New research in mice may explain why certain antibodies could slow or reverse changes in the brain that are characteristic of Alzheimer’s disease. The study used an antibody that targets a particular region on the amyloid-beta protein. Animals injected with the antibody over a period of months developed fewer amyloid plaques in the brain than did control animals. It appears that the antibody draws amyloid-beta out of the brain and into the blood as a clearance mechanism. "Our work is distinguished from previous research in that we have discovered that this particular antibody can be administered into the bloodstream and need not necessarily gain access to the brain and directly attack amyloid plaque to be effective in reducing plaques. Thus, our work suggests a new mechanism by which certain anti-amyloid antibodies could be useful in preventing or treating Alzheimer’s." The research team now is working to understand the detailed mechanism of how the antibody exerts its effect. The research has potential implications for both diagnosis and treatment of Alzheimer’s disease.

DeMattos RB, Bales KR, Cummins DJ, Dodart J-C, Paul SM, Holtzman DM. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease, Proceedings of the National Academy of Sciences Early Edition, 2(27), July 3, 2001.

http://www.eurekalert.org/pub_releases/2001-07/aaft-sgc070201.php

Amyloid plaques follow oxidative damage to brain cells

Research into the causes of Alzheimer's Disease shows that amyloid plaques develop while the illness is taking over the brain but still not clinically evident. Accordingly, the most common scientific belief holds that those plaques contribute to or cause the oxidative damage and inflammation that occur and, ultimately, destroy brain cells. Now, a mouse-model study at the University of Pennsylvania School of Medicine has demonstrated that oxidative damage precedes the plaques. This finding is likely to have significant implications for treatment. "We know Vitamin E, which is an anti-oxidant, can temporarily slow the progression of AD for some patients. What we don't yet know is what will happen if we suppress, reduce or delay oxidative stress over the long run."

Praticò, D., Uryu, K., Leight, S., Trojanoswki, J. Q., & Lee, V. M.-Y. (2001). Increased Lipid Peroxidation Precedes Amyloid Plaque Formation in an Animal Model of Alzheimer Amyloidosis. The Journal of Neuroscience, 21(12), 4183–4187. Retrieved from http://www.jneurosci.org/content/21/12/4183

http://www.eurekalert.org/pub_releases/2001-06/UoPM-Psfr-1406101.php

Scientists begin to unravel cause of blocked memory in Alzheimer's

Researchers at the National Institute of Environmental Health Sciences have found that a protein found in patients with Alzheimer's disease can disrupt brain signals and therefore may contribute to the memory losses of Alzheimer's disease. It appears the characteristic plaques found in the brains of Alzheimer's patients may not be the result of the disease but a cause. It is thought that the major protein of these plaques, beta-amyloid peptide, binds to a receptor in the brain, thus blocking the signals thought to be involved in learning and memory.

Pettit, D. L., Shao, Z., & Yakel, J. L. (2001). β-Amyloid1–42 Peptide Directly Modulates Nicotinic Receptors in the Rat Hippocampal Slice. The Journal of Neuroscience, 21(1), RC120–RC120. Retrieved from http://www.jneurosci.org/content/21/1/RC120

http://www.eurekalert.org/pub_releases/2001-01/NIoE-Ehis-0101101.php

Increased production of protein alpha1-antichymotrypsin found to strongly increase plaque deposits

The protein alpha1-antichymotrypsin can double the accumulation of amyloid plaque in the brains of mice, suggesting a possible new target for therapy in humans. Alpha1-antichymotrypsin (ACT) is a serin protease inhibitor, or serpin, that normally prevents enzymes known as proteases from digesting proteins. Scientists have known for some time that production of ACT is increased in the brains of patients with Alzheimer's disease, but its role has not been understood. The current study, conducted in genetically engineered mice, reveals that increased production of ACT in the brain strongly increases the build-up of amyloid proteins. It is not yet clear exactly how it does this.

Mucke, L., Yu, G.-Q., McConlogue, L., Rockenstein, E. M., Abraham, C. R., & Masliah, E. (2000). Astroglial Expression of Human α1-Antichymotrypsin Enhances Alzheimer-like Pathology in Amyloid Protein Precursor Transgenic Mice. The American Journal of Pathology, 157(6), 2003–2010. doi:10.1016/S0002-9440(10)64839-0

http://www.eurekalert.org/pub_releases/2000-12/UoCS-Rrir-0412100.php

Enzyme found essential for nerve cells to form amyloid plaques

Scientists at Johns Hopkins have demonstrated that a specific enzyme, beta-secretase, is essential for nerve cells to form amyloid plaques, whose over-abundance is characteristic of Alzheimer's. It is one of two enzymes implicated in plaque formation. The other is gamma-secretase. "We're really encouraged by possible therapeutic implications because scientists are already designing small molecules capable of crossing the brain's blood-brain barrier." The molecules could, in theory, be fine-tuned to inhibit such enzymes as beta-secretase.

The research was presented at the annual meeting of the Society for Neuroscience in New Orleans.

http://www.eurekalert.org/pub_releases/2000-11/JHMI-Hsse-0511100.php

Accumulation of plaque may occur because of a decrease in the molecule involved in removing it

While the excess of amyloid plaque deposits have long been recognized as a hallmark of Alzheimer's disease, it has not been known whether the problem occurs because of an over-production, or because of a failure to remove them. A study involving mice found that blood vessels are responsible for removing the beta amyloid protein in healthy brain tissue. In particular, a protein known as LRP-1 (low density lipoprotein receptor-related protein), rapidly shuttles beta amyloid out of the brain and across the blood-brain barrier to the body, which breaks it down into harmless waste products. Not only did the researchers find that removal of amyloid from the brain slowed dramatically when LRP-1 was blocked, but they also showed that healthy middle-aged mice had fewer LRP-1 molecules and shuttled amyloid out of their brains at only half the rate as young mice. It is speculated that healthy young people normally can handle the load of removing amyloid, but that plaques can occur when the LRP-1 system becomes less efficient and the body faces other challenges related to aging, such as decreased circulation. It's also possible that the protein begins accumulating more quickly, overwhelming the removal system.

http://www.eurekalert.org/pub_releases/2000-11/UoR-Simt-0511100.php

ADDLs

Biosensor reveals new information about ADDLs

A new method using nanoscale optical biosensors allows researchers to detect and estimate the size and structure of ADDLs in cerebrospinal fluid. It’s believed that only ADDLs of a certain size cause problems for neurons in the early stages of Alzheimer’s disease. It is hoped that eventually this technology will help us diagnose Alzheimer’s accurately in living people, and aid our understanding of how ADDLs are involved in Alzheimer’s.

Haes, A.J., van Duyne, R.P., Klein, W.L. & Chang, L. 2005. The paper, ANYL 396, was presented at 9:00 a.m., Wednesday, Aug. 31, during the "New Frontiers in Ultrasensitive Analysis: Nanobiotech, Single Molecule Detection, and Single Cell Analysis" symposium.

http://www.eurekalert.org/pub_releases/2005-08/acs-brn081905.php

Findings show how toxic proteins rob Alzheimer's patients of memory

Researchers have discovered a molecular mechanism that could explain why the brain damage in early Alzheimer's disease results in memory loss and not other symptoms such as loss of balance or tremors. Toxic proteins called "amyloid ß-derived diffusible ligands" (ADDLs) — first discovered last year — have been found to specifically attack and disrupt synapses, rather than the neurons themselves. By so doing they damage the neuron’s ability to communicate with other neurons. Moreover, the ADDLs target specific synapses — those where there is a gene linked to memory that is normally expressed. The attack disrupts the normal expression of the gene. The finding brings hope that the damage is reversible. ADDls are a form of amyloid beta, but differ from the better-known amyloid fibrils known as plaques, that are a hallmark of Alzheimer’s.

Lacor, P.N., Buniel, M.C., Chang, L., Fernandez, S.J., Gong, Y., Viola, K.L., Lambert, M.P., Velasco, P.T., Bigio, E.H., Finch, C.E., Krafft, G.A. & Klein, W.L. 2004. Synaptic Targeting by Alzheimer's-Related Amyloid {beta} Oligomers. Journal of Neuroscience, 24, 10191-10200.

http://www.eurekalert.org/pub_releases/2004-12/nu-fsh120104.php

New toxic protein found

New research has found up to 70 times more small, soluble aggregated proteins called "amyloid b-derived diffusible ligands" (ADDLs) in the brain tissue of individuals with Alzheimer's disease compared to that of normal individuals. This supports a recent theory in which ADDLs accumulate at the beginning of Alzheimer's disease and block memory function by a process predicted to be reversible. ADDLs have the ability to attack the memory-building activity of synapses, points of communication where neurons exchange information, without killing neurons. While both are a form of amyloid beta, ADDLs differ significantly from the amyloid fibrils (plaques) that are diagnostic of Alzheimer's. ADDLs are much, much smaller than fibrils. Unlike fibrils, ADDLs are soluble and diffuse between brain cells until they find vulnerable synapses. The discovery of ADDLs may help explain the poor correlation between plaques and neurological deficits.

Gong, Y. et al. 2003. Alzheimer's disease-affected brain: Presence of oligomeric A β ligands (ADDLs) suggests a molecular basis for reversible memory loss. PNAS, 100, 10417-10422.

http://www.eurekalert.org/pub_releases/2003-08/nu-tpc081803.php

Amyloid beta production

Amyloid beta can disrupt neural communication without clumping

Two separate studies have found that minute clumps of amyloid beta (not accumulated into plaque) severely disrupt neurotransmission and inhibit delivery of key proteins in Alzheimer's. One study found that the particles activate an enzyme, CK2, which in turn disrupts the "fast axonal transport" system inside the neuron, while the other found that activation of CK2 blocks neurotransmission at the synapse. It’s suggested that disruptions in the fast axonal transport system are probably key elements in the pathogenesis of Alzheimer's and other adult-onset neurodegenerative diseases, such as Parkinson's and ALS. A prior study also found that activation of another enzyme, GSK3, also disrupts the fast axonal transport system. The new findings suggest the possibility of designing a drug to protect the fast axonal transport system.

Pigino, G. et al. 2009. Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta. PNAS, 106 (14), 5907-5912.

Moreno, H. et al. 2009. Synaptic transmission block by presynaptic injection of oligomeric amyloid beta. PNAS, 106 (14), 5901-5906. Full text at http://www.pnas.org/content/106/14/5901.abstract?sid=14f68dbd-bdda-42c1-8fd5-32ef39913522

http://www.eurekalert.org/pub_releases/2009-03/uoia-moa031709.php
http://www.eurekalert.org/pub_releases/2009-03/mbl-tbt032609.php

Why stroke and hypertension may increase risk of Alzheimer's

New findings of the presence of beta amyloid in the brain of a mouse that overproduces a protein called p25 may help explain the occurrence of sporadic Alzheimer's (the more common form of the disease) and also why stroke and high blood pressure increase the likelihood of developing Alzheimer's. Researchers are now testing potential compounds to halt, or even prevent, the complex cascade of events caused by the presence of p25 that lead to neurodegeneration. The work may also suggest an intervention after stroke to lower or prevent additional risk of Alzheimer's.

The report was presented on June 15 at the annual meeting of the American Society for Biochemistry and Molecular Biology (ASBMB)/8th International Union of Biochemistry and Molecular Biology Conference (IUBMB) in Boston.

http://www.eurekalert.org/pub_releases/2004-06/foas-api060304.php

Gene targeting prevents memory loss in Alzheimer's disease model

A new mouse study presents new evidence that beta-amyloid is directly responsible for causing the memory loss seen in Alzheimer's, and provides compelling evidence for the therapeutic potential of inhibiting an enzyme, beta-secretase (BACE1), required for the production of beta-amyloid. The mice were genetically engineered to lack the enzyme.

Ohno, M., Sametsky, E.A., Younkin, L.H., Oakley, H., Younkin, S.G., Citron, M., Vassar, R. & Disterhoft, J.F. 2004. BACE1 Deficiency Rescues Memory Deficits and Cholinergic Dysfunction in a Mouse Model of Alzheimer's Disease. Neuron, 41, 27-33.

http://www.eurekalert.org/pub_releases/2004-01/nu-gtp010504.php

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