Amyloid-beta Proteins

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.

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.

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.

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.

[3624] Yotter RA, Doshi J, Clark V, Sojkova J, Zhou Y, Wong DF, Ferrucci L, Resnick SM, Davatzikos C. Memory decline shows stronger associations with estimated spatial patterns of amyloid deposition progression than total amyloid burden. Neurobiology of Aging [Internet]. 2013 ;34(12):2835 - 2842. Available from:

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.

[3551] Armstrong A, Mattsson N, Appelqvist H, Janefjord C, Sandin L, Agholme L, Olsson B, Svensson S, Blennow K, Zetterberg H, et al. Lysosomal Network Proteins as Potential Novel CSF Biomarkers for Alzheimer’s Disease. NeuroMolecular Medicine [Internet]. 2014 ;16(1):150 - 160. Available from:

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.

[3614] Vos SJB, Xiong C, Visser PJ, Jasielec MS, Hassenstab J, Grant EA, Cairns NJ, Morris JC, Holtzman DM, Fagan AM. Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study. The Lancet Neurology [Internet]. 2013 ;12(10):957 - 965. Available from:

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.

[3592] Moghekar A, Li S, Lu Y, Li M, Wang M-C, Albert M, O’Brien R. CSF biomarker changes precede symptom onset of mild cognitive impairment. Neurology [Internet]. 2013 . Available from:

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).

[3591] Mielke MM, Savica R, Wiste HJ, Weigand SD, Vemuri P, Knopman DS, Lowe VJ, Roberts RO, Machulda MM, Geda YE, et al. Head trauma and in vivo measures of amyloid and neurodegeneration in a population-based study. Neurology [Internet]. 2014 ;82(1):70 - 76. Available from:

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.

[3569] Doraiswamy MP, Sperling RA, Johnson K, Reiman EM, Wong TZ, Sabbagh MN, Sadowsky CH, Fleisher AS, Carpenter A, Joshi AD, et al. Florbetapir F 18 amyloid PET and 36-month cognitive decline:a prospective multicenter study. Molecular Psychiatry [Internet]. 2014 . Available from:

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.

[3617] Wang L, Brier MR, Snyder AZ, et al. Cerebrospinal fluid aβ42, phosphorylated tau181, and resting-state functional connectivity. JAMA Neurology [Internet]. 2013 ;70(10):1242 - 1248. Available from:

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.

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

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.

[3582] Khan UA, Liu L, Provenzano FA, Berman DE, Profaci CP, Sloan R, Mayeux R, Duff KE, Small SA. Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease. Nature Neuroscience [Internet]. 2014 ;17(2):304 - 311. Available from:

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.

[3555] Bourassa MW, Leskovjan AC, Tappero RV, Farquhar ER, Colton CA, Van Nostrand WE, Miller LM. 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 [Internet]. 2013 ;2(2):129 - 139. Available from:

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.

[3606] Spira AP, Gamaldo AA, An Y, et al. Self-reported sleep and β-amyloid deposition in community-dwelling older adults. JAMA Neurology [Internet]. 2013 ;70(12):1537 - 1543. Available from:

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.

[3626] Zhang W, Thevapriya S, Kim PJ, Yu W-P, Shawn Je H, King Tan E, Zeng L. Amyloid precursor protein regulates neurogenesis by antagonizing miR-574-5p in the developing cerebral cortex. Nature Communications [Internet]. 2014 ;5. Available from:

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.

[3595] Nieznanski K, Surewicz K, Chen S, Nieznanska H, Surewicz WK. Interaction between Prion Protein and Aβ Amyloid Fibrils Revisited. ACS Chemical Neuroscience [Internet]. 2014 ;5(5):340 - 345. Available from:

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.

[3566] Das U, Scott DA, Ganguly A, Koo EH, Tang Y, Roy S. Activity-Induced Convergence of APP and BACE-1 in Acidic Microdomains via an Endocytosis-Dependent Pathway. Neuron [Internet]. 2013 ;79(3):447 - 460. Available from:

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).

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.

[3435] Shen H. Studies cast doubt on cancer drug as Alzheimer's treatment. Nature [Internet]. 2013 . Available from:

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.

[3410] Verghese PB, Castellano JM, Garai K, Wang Y, Jiang H, Shah A, Bu G, Frieden C, Holtzman DM. ApoE influences amyloid-β (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions. Proceedings of the National Academy of Sciences [Internet]. 2013 ;110(19):E1807 - E1816. Available from:

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.

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.

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.

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.

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.

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.

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.

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

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.

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

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

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

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.

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.


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.

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.

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.

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

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.

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.