The Implication of STEP in Synaptic Plasticity and Cognitive Impairments in Alzheimer's Disease and Other Neurological Disorders.

Yacoubou Abdoul Razak Mahaman,Fang Huang,Feiqi Zhu,Kidane Siele Embaye,Xiaochuan Wang

doi:10.3389/fcell.2021.680118

Abstract

STriatal-Enriched protein tyrosine Phosphatase (STEP) is a tyrosine phosphatase that has been implicated in Alzheimer’s disease (AD), the most common form of dementia, and many other neurological diseases. The protein level and activity of STEP have been found to be elevated in most of these disorders, and specifically in AD as a result of dysregulation of different pathways including PP2B/DARPP32/PP1, PKA as well as impairments of both proteasomal and lysosomal systems. The upregulation in STEP leads to increased binding to, and dephosphorylation of, its substrates which are mainly found to be synaptic plasticity and thus learning and memory related proteins. These proteins include kinases like Fyn, Pyk2, ERK1/2 and both NMDA and AMPA receptor subunits GluN2B and GluA2. The dephosphorylation of these molecules results in inactivation of these kinases and internalization of NMDA and AMPA receptor complexes leading to synapse loss and cognitive impairments. In this study, we aim to review STEP regulation and its implications in AD as well as other neurological disorders and then summarize data on targeting STEP as therapeutic strategy in these diseases.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia and is characterized by a gradual loss of short-term memory and a progressive decline of cognitive functions
From the data reviewed in this study, it is evident that increased STriatal-Enriched protein tyrosine Phosphatase (STEP) as a result of alteration of ubiquitin proteasome system (UPS), increased translation, as well as decreased phosphorylation (PKA and phosphatase 1 (PP1)) has been implicated in many neuropsychiatric diseases
They include, but are not limited to, GluN2B, GluA2, GluA3, ERK1/2, p38, Fyn, Pyk2 and SPIN90. These alterations lead to internalization of NMDA and AMPA receptors, collapse and loss of dendritic spines together culminating into synaptic plasticity and learning and memory impairments, which are expressed in human patients and animal models of these diseases as cognitive deficits

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia and is characterized by a gradual loss of short-term memory and a progressive decline of cognitive functions. It has been a major public health problem in modern society which will undoubtedly increase dramatically in the coming years, unless drugs that can prevent or cure the disease become available. The two main histopathological hallmarks of AD are extracellular deposit of amyloid beta (Aβ) forming senile plaques, and intracellular hyperphosphorylated tau forming neurofibrillary tangles (Bennett et al, 2004). Due to failure of many tau and Aβ based

Objectives

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Conclusion