Recent research has closed a lot of gaps in our understanding and has helped show how memories get destroyed.

Beta-amyloid binds to a protein called PirB that leads to signaling cascade that ultimately leads to the destruction of synapses, and eradicates memories in the process.

This helps explain why people can have memory problems before beta-amyloid clumps into plaques.

PirB is used to help destroy synaptic connections — and sometimes that’s necessary. However, when beta-amyloid binds to it, it destroys a lot more connections than it should, resulting in memory losses.

Here are some excerpts from an article about the recent research:

Scientists at the Stanford University School of Medicine have shown how a protein fragment known as beta-amyloid, strongly implicated in Alzheimer’s disease, begins destroying synapses before it clumps into plaques that lead to nerve cell death.

Beta-amyloid begins life as a solitary molecule but tends to bunch up — initially into small clusters that are still soluble and can travel freely in the brain, and finally into the plaques that are hallmarks of Alzheimer’s. The study showed for the first time that in this clustered form, beta-amyloid can bind strongly to a receptor on nerve cells, setting in motion an intercellular process that erodes their synapses with other nerve cells.

Using an experimental mouse strain that is highly susceptible to the synaptic and cognitive impairments of Alzheimer’s disease, Shatz and her colleagues showed that if these mice lacked a surface protein ordinarily situated very close to synapses, they were resistant to the memory breakdown and synapse loss associated with the disorder. The study demonstrated for the first time that this protein, called PirB, is a high-affinity receptor for beta-amyloid in its “soluble cluster” form, meaning that soluble beta-amyloid clusters stick to PirB quite powerfully. That trips off a cascade of biochemical activities culminating in the destruction of synapses.

PirB, previously thought to be used only by cells in the immune system, is also found on nerve cells in the brain, where it slows the ability of synapses to strengthen in proportion to the extent to which they are engaged, and actually promotes their weakening. Such brakes are desirable in the brain because too-easy synaptic strength-shifting could trigger untoward consequences like epilepsy.

a particular mouse brain region, whose constituent synapses are normally quite nimble at shifting their relative strengths in response to early-life experiences, showed no such flexibility in young Alzheimer’s-prone mice.

Maybe PirB and beta-amyloid were binding. This might cause PirB to stomp on the brakes even more than it usually does, weakening synapses so much they could disappear altogether, taking memories with them.

Further experiments showed that, indeed, beta-amyloid binds strongly to PirB. While PirB is specifically a mouse protein, Kim also identified for the first time an analogous beta-amyloid receptor in the human brain: a protein called LilrB2.[1]

Other proteins are involved in this pathway where in memories are destroyed:

Cofilin works by breaking down actin, a building-block protein essential to maintaining synaptic structure. And, as the new study also showed, beta-amyloid’s binding to PirB results in biochemical changes to cofilin that revs up its actin-busting, synapse-disassembling activity.[1]

There are drug development possibilities as a result of this research:

Shatz suggested that drugs that block beta-amyloid’s binding to PirB on nerve-cell surfaces — for example, soluble PirB fragments containing portions of the molecule that could act as decoy — might be able to exert a therapeutic effect. “I hope this finding will be enticing enough to pharmaceutical and biotechnology companies that someone will try pushing this idea forward,” she said.[1]

The two most common isoforms of beta-amyloid are Aβ40 and Aβ42. People who are more likely to get Alzheimers are more likely to produce the latter isoform in greater proportion. One can imagine any number of genetic pathways involved in the overproduction of this isoform — and the overproduction of beta-amyloid in general. One can also imagine different isoforms of the PirB analog in humans. At this point, further research is needed to detail all those potential pathways and then stop them in their tracks. If that can be done, people’s memories won’t be destroyed. And many people and their loved ones’ lives will be better as a result.

Also, although amyloid beta monomers do show some affinity for PirB, amyloid beta oligomers bind more strongly. “Relative to monomeric Aβ42, oligomerized Aβ42 peptides bound to PirB-expressing cells about 6 times as much.”[1] This suggests that Alzheimers therapies that target oligomers may be helpful in reducing PirB-mediated decline.[2]

[1] Scientists reveal how beta-amyloid may cause Alzheimer’s

Journal Reference:

  1. Kim T, Vidal GS, Djurisic M, William CM, Birnbaum ME, Garcia KC, Hyman BT, and Shatz CJ. Human LilrB2 is a beta-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer's model.Science, September 2013 DOI: 10.1126/science.1242077
Footnotes

[1] https://www.ncbi.nlm.nih.gov/pmc...

[2] Alzheimer's Therapeutics Targeting Amyloid Beta 1–42 Oligomers II: Sigma-2/PGRMC1 Receptors Mediate Abeta 42 Oligomer Binding and Synaptotoxicity

 

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