β-Amyloid: the key peptide in the pathogenesis of Alzheimer's disease.

Xiaojuan Sun,Wei-Dong Chen,Yan-Dong Wang

doi:10.3389/fphar.2015.00221

Abstract

The amyloid β peptide (Aβ) is a critical initiator that triggers the progression of Alzheimer’s Disease (AD) via accumulation and aggregation, of which the process may be caused by Aβ overproduction or perturbation clearance. Aβ is generated from amyloid precursor protein through sequential cleavage of β- and γ-secretases while Aβ removal is dependent on the proteolysis and lysosome degradation system. Here, we overviewed the biogenesis and toxicity of Aβ as well as the regulation of Aβ production and clearance. Moreover, we also summarized the animal models correlated with Aβ that are essential in AD research. In addition, we discussed current immunotherapeutic approaches targeting Aβ to give some clues for exploring the more potentially efficient drugs for treatment of AD.

Highlights

Alzheimer’s disease (AD), known as Senile Dementia, is a most common age-related neurodegenerative disorder
Continuous amyloid β peptide (Aβ) aggregation or sustained elevation of Aβ would cause a chronic response of the innate immune system by activating microglia through some immunological receptors such as Toll-like Receptors 2 (TLR2), TLR4, TLR6, their coreceptors CD14, CD36, and CD47, which can probably destroy functional neurons by direct phagocytosis (Weggen et al, 2001; Neniskyte et al, 2011; Liu et al, 2012)
Aβ accumulation induced by expression the human amyloid precursor protein (APP) carrying both the Swedish and Indiana mutation under the control of the murine Thy 1.2 promoter

Summary

Introduction

Alzheimer’s disease (AD), known as Senile Dementia, is a most common age-related neurodegenerative disorder. Continuous Aβ aggregation or sustained elevation of Aβ would cause a chronic response of the innate immune system by activating microglia through some immunological receptors such as Toll-like Receptors 2 (TLR2), TLR4, TLR6, their coreceptors CD14, CD36, and CD47, which can probably destroy functional neurons by direct phagocytosis (Weggen et al, 2001; Neniskyte et al, 2011; Liu et al, 2012) It results in inflammatory response, concomitantly releasing a lot of inflammation related mediators including complement factors, eicosanoids, chemokines, and proinflammatory cytokines, which can impair microglial clearance of Aβ and the neuronal debris and increase microglia-mediated neuronal death and loss of neuronal synapses, contributing greatly to AD pathogenesis. Induction of another degrading pathway of autophagy serves to accelerate the clearance of both soluble Aβ and Aβ aggregates (Nixon, 2007)

Animal Models Related with Aβ for AD

Caenorhabditis elegans Drosophila Mouse

Overviews of Current Therapeutics Targeting Aβ

Findings

Conclusion and Perspectives