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Amyloid beta hypothesis could be wrong
Posted: Wednesday, December 21, 2016 8:51 AM
Joined: 9/13/2013
Posts: 112

Year in review: Alzheimer's drug may clarify disease origin     12/14/2016

Could it be caused by pathogen -

Alzheimer's protein may help brain fight infection    5/25/2016

Human amyloid-beta acts as natural antibiotic in the brains of animal models     5/25/2016 MGH press release

PBS Interview with Dr Rob Moir

Lane Simonian
Posted: Wednesday, December 21, 2016 10:46 AM
Joined: 12/12/2011
Posts: 4906

The brain seems to have two responses to infections: one is to form plaques; the other is to produce oxidants such as hydrogen peroxide and peroxynitrite.  The former may entomb pathogens; the oxidants may end up doing a lot of collateral damage.

There are three other ways in which plaques may be neuroprotective.  One is by entombing copper and zinc, it may stop the production of hydrogen peroxide.  This may be what stops Alzheimer's from becoming a prion disease.

Mature amyloid fibrils derived from Abeta-(1–40) did not generate hydrogen peroxide. We conclude that hydrogen peroxide formation during the early stages of protein aggregation may be a common mechanism of cell death in these (and possibly other) neurodegenerative diseases. 

Secondly, amyloid plaques may absorb amyloid oligomers which during the early stages of Alzheimer's disease may add to oxidative stress.

Oligomers and beta-amyloid fibers induce nitro oxidative stress, triggering the production of nitric oxide and free radicals in the extracellular environment. When they combine, peroxynitrite is produced, a highly reactive molecule that can modify proteins and alter their function. The study led by Francisco José Muñoz reveals that when peroxynitrite reacts with beta-amyloid oligomers, it facilitates its stabilization and prevents the formation of mature fibers. Thus, the more beta-amyloid protein there is, the more peroxynitrite formation is promoted and the latter, in turn, makes the beta-amyloid oligomers to remain stabilized, perpetuating the characteristic neuronal damage of Alzheimer's disease.


Thirdly, amyloid plaques around neurons inhibit the formation of amyloid plaques in blood vessels and the latter rather than the former are a source of oxidative stress (many of the genes that cause early onset Alzheimer's disease result in plaques in blood vessels rather than in neurons).

Early-onset Formation of Parenchymal Plaque Amyloid Abrogates Cerebral Microvascular Amyloid Accumulation in Transgenic Mice* 

If you scavenge peroxynitrite, you end up with fewer oligomers and more plaques in neurons and contrary to the dominant hypothesis in the field--no Alzheimer's disease.  On the other hand if you remove plaques you may end with more plaques in blood vessels potentially leading to microbleeds and brain swelling.  Removing the plaques in neurons likely does little good and can do harm; removing the oligomers may only help slow down the progression of Alzheimer's disease very early on (as results from the aducanumab study seem to indicate).