The Molecular Mechanisms of Neuroinflammation in Alzheimer’s Disease, the Consequence of Neural Cell Death

Abstract

Alzheimer’s disease (AD) is accompanied by neural cell loss and memory deficit. Neural cell death, occurring via apoptosis and autophagy, is widely observed in the AD brain in addition to neuroinflammation mediated by necroptosis and the NLRP3 inflammasome. Neurotoxicity induced by amyloid-beta (Aβ) and tau aggregates leads to excessive neural cell death and neuroinflammation in the AD brain. During AD progression, uncontrolled neural cell death results in the dysregulation of cellular activity and synaptic function. Apoptosis mediated by pro-apoptotic caspases, autophagy regulated by autophagy-related proteins, and necroptosis controlled by the RIPK/MLKL axis are representative of neural cell death occurred during AD. Necroptosis causes the release of cellular components, contributing to the pro-inflammatory environment in the AD brain. Inordinately high levels of neural cell death and pro-inflammatory events lead to the production of pro-inflammatory cytokines and feed-forward hyper neuroinflammation. Thus, neural cell death and neuroinflammation cause synaptic dysfunction and memory deficits in the AD brain. In this review, we briefly introduce the mechanisms of neural cell death and neuroinflammation observed in the AD brain. Combined with a typical strategy for targeting Aβ and tau, regulation of neural cell death and neuroinflammation may be effective for the amelioration of AD pathologies.

Mushroom-derived bioactive components with definite structures in alleviating the pathogenesis of Alzheimer’s disease

“…In 1992, John Hardy et al introduced the Aβ cascade hypothesis, which has since undergone a gradual process of refinement and improvement ( Hur, 2022 ). According to the prevailing perspective of this hypothesis, Aβ is a polypeptide generated through the ongoing hydrolysis of APP under the influence of β secretases and γ secretases ( Choi et al, 2023 ). These Aβ fragments can precipitate and aggregate within the cellular matrix, eventually leading to the formation of senile plaques ( Zhang, Lin, et al, 2022 ).…”

Neuroinflammation: A Critical Factor in Neurodegenerative Disorders

“…Stage seven occurs when a person is terminally ill and exhibiting motor symptoms, communication difficulties, and the need for feeding help (Figure 2) [25]. Reproduced under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/) from Choi et al [26]. Copyright © 2023 by the authors.…”

Gut–Brain Axis: Focus on Sex Differences in Neuroinflammation

“…The activation of tumor necrosis factor/nerve growth factor (TNF/NGF) receptors recruits caspase-8, forming the death-initiating signaling complex (DISC), which leads to apoptosis. However, when caspase-8 is inhibited, receptor-interacting protein (RIP) kinases 1 and 3 (RIPK1 and RIPK3) form the necrosome and initiate necroptosis [48]. A necrosomemediated activation of NLRP3 inflammasome, which is negatively regulated by caspase-8, takes part in the molecular pathogenesis of AD [49,50].…”