Neuronal cell death mechanisms in Alzheimer's disease: An insight

Abstract

Regulated cell death (RCD) is an ordered and tightly orchestrated set of changes/signaling events in both gene expression and protein activity and is responsible for normal development as well as maintenance of tissue homeostasis. Aberrant activation of this pathway results in cell death by various mechanisms including apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death. Such pathological changes in neurons alone or in combination have been observed in the pathogenesis of various neurodegenerative diseases including Alzheimer's disease (AD). Pathological hallmarks of AD focus primarily on the accumulation of two main protein markers: amyloid β peptides and abnormally phosphorylated tau proteins. These protein aggregates result in the formation of A-β plaques and neuro-fibrillary tangles (NFTs) and induce neuroinflammation and neurodegeneration over years to decades leading to a multitude of cognitive and behavioral deficits. Autopsy findings of AD reveal massive neuronal death manifested in the form of cortical volume shrinkage, reduction in sizes of gyri to up to 50% and an increase in the sizes of sulci. Multiple forms of cell death have been recorded in neurons from different studies conducted so far. However, understanding the mechanism/s of neuronal cell death in AD patients remains a mystery as the trigger that results in aberrant activation of RCD is unknown and because of the limited availability of dying neurons. This review attempts to elucidate the process of Regulated cell death, how it gets unregulated in response to different intra and extracellular stressors, various forms of unregulated cell death, their interplay and their role in pathogenesis of Alzheimer's Disease in both human and experimental models of AD. Further we plan to explore the correlation of both amyloid-beta and Tau with neuronal loss as seen in AD.

Keywords: Alzheimer’s disease; apoptosis; autophagy; ferroptosis; necroptosis.

FIGURE 1

Schematic representation of cell death mechanisms responsible for neuronal death in AD. (Created with BioRender.com.) Apoptosis – initiated inner mitochondrial membrane changes leads to release of cytochrome c, AIF, Smac/DIABLO, HtrA2/Omi, activates effector caspases and causes apoptotic cell death. Necroptosis – is a form of RCD involving RIPK1, RIPK3, necrosome formation and MLKL activation. Another form of necrosis mPTP leading to rupture of outer membrane and non-specific release of intermembrane space proteins into cytosol, causing cell death. Autophagy – another cell death mechanism mediated by Beclin 1, HSC70, LAMP2A leads to formation of LC3II autolysosomes causing cell death. Pyroptosis – lytic form of cell death associated with inflammasomes formation, activation caspase-1/4/5 Gasdermin-D cleavage and release of inflammatory cytokines is also responsible for neuronal cell death in AD. Ferroptosis – Iron-dependent mode of cell death, induced by diverse triggers involves ROS, lipid peroxide accumulation depleted glutathione levels.