The dark sides of amyloid in Alzheimer's disease pathogenesis

Abstract

a b s t r a c tAlthough widely explored, the pathogenesis of Alzheimer's disease (AD) has yet to be cleared. Over the past twenty years the so call amyloid cascade hypothesis represented the main research paradigm in AD pathogenesis. In spite of its large consensus, the proposed role of b-amyloid (Ab) remain to be elucidated. Many evidences are starting to cast doubt on Ab as the primary causative factor in AD. For instance, Ab is deposited in the brain following many different kinds of injury. Also, concentration of Ab needed to induce toxicity in vitro are never reached in vivo. In this review we propose an amyloid-independent interpretation of several AD pathogenic features, such as synaptic plasticity, endo-lysosomal trafficking, cell cycle regulation and neuronal survival.

Ten Challenges of the Amyloid Hypothesis of Alzheimer’s Disease

“…The ultimate test of any disease theory, the development of medicine from the principles of the ruling paradigm, has not yet been successful [7][12]; the absence of any Aβ-centric drug on the market or indeed any successful phase 3 trial has led to calls for modification of the amyloid hypothesis [11]. The most promising current drug candidates are antibodies such as solanezumab that target various Aβ forms [136].…”

“…Neuro-degeneration and cognitive decline does not correlate with the amount of A plaques [11,12]. Also, 20−40% of cognitively normal people have A plaques in amounts typical for the disease [70].…”

“…Accordingly, our ability to treat the disease remains deeply unsatisfactory, with current treatments only delaying disease progression by months [10] [11].…”

Beta-Amyloid Plasma Levels in Adolescents with Anorexia Nervosa of the Restrictive Type

“…The Aβ peptide has been predominantly investigated in the field of Alzheimer's disease and considered as the most probable initial culprit of this disease, specifically in the so-called ‘amyloid hypothesis' [3]. According to this model, Aβ aggregation in oligomers and subsequent accumulation in plaques have been variously connected to degeneration and subsequent death of neurons in Alzheimer's disease patients, mainly in the hippocampus and cortex [3].…”

“…β-Amyloid (Aβ) peptides (from 36 up to 43 amino acids), the proteolytic products of a precursor membrane protein, amyloid precursor protein (APP) expressed in the CNS as well as other tissues, are chiefly known to aggregate and accumulate in neurodegenerative disorders, primarily in Alzheimer's disease [3]. In addition, Aβ and other APP fragments play a role in the physiology of synaptic transmission, neuronal migration and outgrowth [4,5], suggesting that a dysfunction of Aβ signalling might be potentially operative in those synaptopathies expressing without overt neurodegenerative phenomena, as most psychiatric diseases are thought to be [6].…”