Amyloid-Beta and Phosphorylated Tau Accumulations Cause Abnormalities at Synapses of Alzheimer’s disease Neurons

Abstract

Amyloid Beta (Aβ) and hyperphosphorylated tau are hallmark lesions of Alzheimer disease (AD). However, the loss of synapses and dysfunctions of neurotransmission are more directly tied to disease severity. The role of these lesions in the pathoetiological progression of the disease remains contested. Biochemical, cellular, molecular and pathological studies provided several lines of evidence and improved our understanding of how amyloid beta and hyperphosphorylated tau accumulation may directly harm synapses and alter neurotransmission. In-vitro evidence suggests that amyloid beta and hyperphosphorylated tau have both direct and indirect cytotoxic effects that affect neurotransmission, axonal transport, signaling cascades, organelle function, and immune response in ways that lead to synaptic loss and dysfunctions in neurotransmitter release. Observations in preclinical models and autopsy studies support these findings, suggesting that while the pathoetiology of positive lesions remains elusive, their removal may reduce disease severity and progression. The purpose of this article is to highlight the need for further investigation of the role of tau in disease progression and its interactions with Aβ and neurotransmitters alike.

Overexpression of let-7a increases neurotoxicity in a PC12 cell model of Alzheimer's disease via regulating autophagy

“…Increasing evidence has suggested that the abnormal accumulation of Aβ may induce marked cytotoxicity in neurons and is a key pathogenic factor of AD (26)(27)(28). In the present study, an Aβ peptide, Aβ1-40, was used to investigate the mechanism of Aβ neurotoxicity.…”

A Critical Assessment of Research on Neurotransmitters in Alzheimer’s Disease

“…Ravi Rajmohan and P. Hemachandra Reddy discuss the involvement of Aβ and hyperphosphorylated tau in neurotransmitter pathology, in AD [17]. They cover biochemical, cellular, molecular, and pathological studies of Aβ and hyperphosphorylated tau accumulation in AD neurons, and how Aβ and hyperphosphorylated tau lesions directly damage synapses and alter neurotransmission.…”

Extracellular Chaperones in Neuronal Proteinopathies: Protecting and Facilitating Neuronal Function

“…27 Further details about the role of tau in AD progression have been discussed elsewhere. 28 Similarly, Parkinson disease (PD) is marked by the accumulation of α-synuclein leading to Lewy body formation in the substantia nigra, 29 and Huntington disease (HD) is characterised by …”

“…28 Furthermore, prion diseases (rare neurodegenerative diseases) are characterised by the aggregation of pathogenic prion protein (PrP c ). 24 However, in case of amyotrophic lateral sclerosis (ALS) instead of fibrillary amyloid deposits, the pathological characteristic includes different inclusion bodies such as ubiquitinated, hyaline, and skein-like inclusions and those of the Bunina bodies 24 (Figure 1).…”