Research suggests that brain abnormalities associated with Alzheimer's can be induced by propagating Amyloid-b misfolded protein.

Misfolded Abeta’s Link to Alzheimer’s

scan of abeta Amyloid b Deposition in Alzheimer's Disease
Research suggests that brain abnormalities associated with Alzheimer's can be induced by propagating Amyloid-b misfolded protein.

Originally Posted on Molecular Psychiatry | 4 October 2011

Alzheimer’s disease (AD), the most common type of senile dementia, is associated with misfolded Abeta (amyloid-b or Ab) build-up in the brain. Although compelling evidence indicates that the misfolding and oligomerization of Ab is the triggering event in AD, the mechanisms responsible for the initiation of Ab accumulation are unknown. This study shows that Amyloid-b deposition can be induced by injecting AD brain extracts into animals, which will never develop these alterations without exposure to this material.

The accumulation of Amyloid-b (Ab) deposits increased progressively with the time after inoculation, and the Ab lesions were observed in brain areas far from the injection site. Our results suggest that a prion-like disease transmission mechanism can induce some of the typical brain abnormalities associated with Alzheimer’s by propagating misfolded proteins. These findings may have broad implications for understanding the molecular mechanisms responsible for Alzheimer’s initiation and may help develop new disease prevention strategies and intervention strategies.

Alzheimer‚Äôs disease is the most common type of senile dementia, mainly affecting individuals over 65. Disease manifestation is characterized by progressive impairment of memory and cognition, principally produced by synaptic dysfunction and neuronal loss. The disease’s etiology is currently unknown, and it is a matter of great interest, as more than 90% of Alzheimer’s cases arise sporadically.

Cerebral accumulation of misfolded aggregates composed of the amyloid-b (Ab) protein and hyper-phosphorylated tau have long been associated with the disease. Compelling evidence suggests that misfolding and aggregation of Amyloid-b (Ab) might be the triggering event responsible for inducing the subsequent brain abnormalities.

However, it is currently unknown why Amyloid-b  (Ab), a naturally produced protein, begins to misfold and aggregate in the brain.

Interestingly, brain accumulation of misfolded protein aggregates is a common feature of several neurodegenerative diseases, including Alzheimer’s, Parkinson‚Äôs disease, Huntington‚Äôs disease, and amyotrophic lateral sclerosis, and prion disorders.¬† These diseases can have a sporadic or inherited origin, except in prion diseases, in which the pathology can be transmitted by infection.

Strikingly, the infectious agent responsible for prion diseases is composed exclusively of the misfolded and aggregated form of the prion protein that has the surprising ability to propagate the disease through an infection process auto-catalytic conversion of the normal host prion protein.

Extensive in vitro studies have shown that disease-associated misfolding and aggregation of proteins follow a seeding-nucleation model. The formation of oligomeric seeds is a slow and rate-determining event. In this model, protein misfolding and aggregation are greatly accelerated by the addition of pre-formed seeds. The seeding/nucleation mechanism offers a plausible explanation for the transmissibility of prion diseases by infectious misfolded prion protein and predicts that other misfolded proteins have the potential to transmit the disease through a prion-like infectious process.8

Exciting recent studies have reported that Amyloid-b (Ab) deposition can be accelerated in vivo by injecting AD brain homogenates carrying Ab aggregates.

These studies have been done in transgenic mice expressing a mutant form of the human amyloid precursor protein (APP), which spontaneously develop Alzheimer’s-like neuropathological alterations. Thus, the induction of Amyloid-b (Ab) deposition observed in these studies only represents an acceleration of a few months of the spontaneous process that was set to occur by introducing the mutant gene.

This is drastically different from the bonafide infectious process produced by prions in animals, which would not spontaneously develop the disease without inoculation with the misfolded protein. This study aims to demonstrate that similar to prion diseases, and an AD-like pathology can be induced in animal models that naturally do not develop amyloid aggregates during their lifespan.


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