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Amyloid-b Deposition in Alzheimer’s Disease

By March 30, 2018 One Comment

Originally Posted on Molecular Psychiatry | 4 October 2011

scan of abeta Amyloid b Deposition in Alzheimer's Disease

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

The accumulation of 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 some of the typical brain abnormalities associated with AD can be induced by a prion-like mechanism of disease transmission through propagation of misfolded proteins. These findings may have broad implications for understanding the molecular mechanisms responsible for the initiation of AD, and may contribute to the development of new strategies for disease prevention and intervention.

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

Cerebral accumulation of misfolded aggregates composed of the amyloid-b (Ab) protein and hyper-phosphorylated tau have long been associated to the disease. Compelling evidence suggest that misfolding and aggregation of Ab might be the triggering event, which is responsible for inducing the subsequent brain abnormalities. However, it is currently unknown why Ab, which is a naturally produced protein, begin to misfold and aggregate in the brain. Interestingly, brain accumulation of misfolded protein aggregates is a common feature of several neurodegenerative diseases, including, besides AD, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and prion disorders. These diseases can have sporadic or inherited origin, except in case of prion diseases, in which the pathology can be transmitted by infection. Strikingly, the infectious agent responsible for prion diseases is composed exclusively by the misfolded and aggregated form of the prion protein that has the surprising ability to propagate the disease through an infection process, which involve the 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 in which the formation of oligomeric seeds is a slow and rate-determining event. In this model, protein misfolding and aggregation is greatly accelerated by 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 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 AD-like neuropathological alterations. Thus, the induction of Ab deposition observed in these studies only represents an acceleration of few months of the spontaneous process that was set to occur by introduction of the mutant gene. This is drastically different from the bona fide infectious process produced by prions in animals, which, without inoculation with the misfolded protein, would not spontaneously develop the disease. The goal of this study is to demonstrate that similar to prion diseases, an AD-like pathology can be induced in animal models that naturally do not develop amyloid aggregates during their lifespan.

 

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