Brain proteins involved in the development of Alzheimer's

  • When a particular fat molecule in the brain doesn't break down properly, cognition gets harder, and there's an increase in amyloid precursor proteins (which are part of the Alzheimer's cascade).
  • Tau proteins are also involved in the Alzheimer's cascade. A new study shows that individuals vary markedly in how quickly they spread in the brain.
  • A protein called SIRT6 has now been found to be crucially involved in DNA repair, to be severely deficient in those with Alzheimer's, and to be associated with learning impairment in mice.
  • A protein called NPTX2 may explain why some brains can cope with high levels of amyloid-beta much better than others.

Disrupted fat breakdown in the brain involved in Alzheimer’s?

The brain is rich in lipids (fats), which not only help insulate nerve fibers, but are also a crucial part of the membranes surrounding brain cells. One particular type that is highly enriched in the brain (sphingolipids) produces something called S1P. A mouse study has now found that when their brains were blocked from breaking down S1P, the mice began to show learning and memory problems. Moreover, there was a significant increase in the amount of APP (the precursor of amyloid-beta proteins, characteristic of Alzheimer’s) in their brains.

The problem is that S1P is broken down into simpler products, one of which is vital for autophagy — how cells digest and recycle their own components, when they don’t work properly. This finding suggests a new mechanism for the development of Alzheimer's and other dementias.

https://www.eurekalert.org/pub_releases/2017-05/uob-dfb051917.php

Spread of tau protein measured in Alzheimer's brains

A study involving 16 patients at different stages of Alzheimer's disease, who underwent memory tests and PET scans at 17-month intervals, has found a marked difference between individuals in how much tau protein is in the brain and how quickly it spreads. Moreover, there was a strong correlation between the amount of tau and how much episodic memory was impaired.

This may help explain why Alzheimer's progresses at such different rates between people.

https://www.eurekalert.org/pub_releases/2017-05/ki-sot051617.php

Low levels of protein SIRT6 implicated in Alzheimer's

It’s generally thought that aging is the result of DNA damage accumulation, because of the breakdown in DNA repair processes. A new mouse study has found that a crucial element in DNA repair is a protein called SIRT6. Mice deficient in SIRT6 showed marked learning impairments, and their brains showed more DNA damage, cell death, and hyperphosphorylated tau (a critical mark in several neurodegenerative diseases, as well as Alzheimer's).

Humans with Alzheimer's disease were also found to have a severe deficiency of the SIRT6 protein.

It’s suggested that SIRT6 loss, leading to DNA damage accumulation, may be the beginning of the chain that ends in Alzheimer’s and other neurodegenerative disease.

https://www.eurekalert.org/pub_releases/2017-05/aabu-bur050517.php

Low levels of 'memory protein' linked to cognitive decline in Alzheimer's disease

We know that high levels of amyloid-beta plaques are characteristic of Alzheimer's, but we also know that people can have high levels of amyloid without displaying symptoms of Alzheimer's. A new study shows that the reason for this apparent discrepancy may lie with another protein, called NPTX2.

It appears that memory loss occurs when high amyloid-beta occurs in combination with low levels of NPTX2.

The gene which expresses the protein NPTX2 belongs to a set of genes known as "immediate early genes," which are activated almost instantly in brain cells when an experience results in a new memory. The protein is used by neurons to strengthen the circuits that encode memories.

A study of 144 archived human brain tissue samples revealed that NPTX2 protein levels were reduced by as much as 90% in brain samples from people with Alzheimer's compared with age-matched brain samples without Alzheimer's. People with amyloid plaques who had never shown signs of Alzheimer's, on the other hand, had normal levels of NPTX2.

A mouse study then confirmed this link, by showing that cell function wasn’t affected by a lack of NPTX2 until a gene that increases amyloid generation was added. With both amyloid and no NPTX2, fast-spiking interneurons could not control brain "rhythms" which synchronize activity between neurons, thus creating circuits / networks that encode memories. Additionally, a glutamate receptor essential for interneuron function was also reduced — as it was in the human Alzheimer's brains.

A study of NPTX2 protein levels in the cerebrospinal fluid (CSF) of 60 living Alzheimer's patients and 72 controls found that

  • NPTX2 levels were 36-70% lower in people with Alzheimer's
  • lower cognitive scores were associated with lower levels of NPTX2
  • NPTX2 levels were more closely correlated with cognitive performance that tau proteins and amyloid-beta
  • NPTX2 correlated with the size of the hippocampus

https://www.eurekalert.org/pub_releases/2017-04/jhm-llo042417.php

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