The Physiological Roles of Amyloid-β Peptide Hint at New Ways to Treat Alzheimer's Disease

Abstract

Amyloid-ß (Aß) is best known as the misfolded peptide that is involved in the pathogenesis of Alzheimer's disease (AD), and it is currently the primary therapeutic target in attempts to arrest the course of this disease. This notoriety has overshadowed evidence that Aß serves several important physiological functions. Aß is present throughout the lifespan, it has been found in all vertebrates examined thus far, and its molecular sequence shows a high degree of conservation. These features are typical of a factor that contributes significantly to biological fitness, and this suggestion has been supported by evidence of functions that are beneficial for the brain. The putative roles of Aß include protecting the body from infections, repairing leaks in the blood-brain barrier, promoting recovery from injury, and regulating synaptic function. Evidence for these beneficial roles comes from in vitro and in vivo studies, which have shown that the cellular production of Aß rapidly increases in response to a physiological challenge and often diminishes upon recovery. These roles are further supported by the adverse outcomes of clinical trials that have attempted to deplete Aß in order to treat AD. We suggest that anti-Aß therapies will produce fewer adverse effects if the known triggers of Aß deposition (e.g., pathogens, hypertension, and diabetes) are addressed first.

Do Post-Translational Modifications Influence Protein Aggregation in Neurodegenerative Diseases: A Systematic Review

“…Two proteases that act on APP, a β-secretase and γ-secretase, yield the Aβ 40 and Aβ 42 isoforms, respectively. Alternatively, APP may be processed by α-secretase via the non-amyloidogenic pathway [35][36][37]. While Aβ is believed to play a number of physiological roles, including regulation of synaptic activity [36,37], in AD, it acquires a toxic gain-of-function, undergoes oligomerisation and aggregation, eventually forming insoluble, fibrillar, senile plaques that are central to neurotoxicity and neurodegeneration [2,38,39].…”

Ameliorating amyloid aggregation through osmolytes as a probable therapeutic molecule against Alzheimer's disease and type 2 diabetes

“…Ab serves various physiological functions in humans, such as being involved in antimicrobial action, tumor suppression, sealing exposures in the bloodbrain barrier, encouraging recovery from brain injury, and rectifying synaptic function. 89 hIAPP serves as part of the endocrine pancreas, helping with glycemic control, and is a synergistic ally of insulin and the bone metabolism. 90 However, both Ab and hIAPP have shown conformational changes in their monomeric states that can lead to amyloid aggregation, which is crucial to the pathology of AD and T2D.…”

Alzheimer’s disease-related dysregulation of protein synthesis causes key pathological features with ageing

“…Several lines of evidence suggest that prior to inducing neurotoxicity Aβ1-42 can function as a beneficial agent 60 , with its functions ranging from anti-microbial to enhancement of long-term potentiation and memory, akin to a neurotrophic factor. Our finding that nanomolar doses of Aβ1-42 enhance translation overall, via a pathway also modulated by the neurotrophin BDNF 61 , lends support to this idea.…”