Endo-lysosomal pathway and ubiquitin-proteasome system dysfunction in Alzheimer's disease pathogenesis

Abstract

Several lines of evidence have shown that defects in the endo-lysosomal autophagy degradation pathway and the ubiquitin-proteasome system play a role in Alzheimer’s Disease (AD) pathogenesis and pathophysiology. Early pathological changes, such as marked enlargement of endosomal compartments, gradual accumulation of autophagic vacuoles (AVs) and lysosome dyshomeostasis, are well-recognized in AD. In addition to these pathological indicators, many genetic variants of key regulators in the endo-lysosomal autophagy networks and the ubiquitin-proteasome system have been found to be associated with AD. Furthermore, altered expression levels of key proteins in these pathways have been found in AD human brain tissues, primary cells and AD mouse models. In this review, we discuss potential disease mechanisms underlying the dysregulation of protein homeostasis governing systems. While the importance of two major protein degradation pathways in AD pathogenesis has been highlighted, targeted therapy at key components of these pathways has great potential in developing novel therapeutic interventions for AD. Future investigations are needed to define molecular mechanisms by which these complex regulatory systems become malfunctional at specific stages of AD development and progression, which will facilitate future development of novel therapeutic interventions. It is also critical to investigate all key components of the protein degradation pathways, both upstream and downstream, to improve our abilities to manipulate transport pathways with higher efficacy and less side effects.

Targeting Ubiquitin-Proteasome Pathway by Natural Products: Novel Therapeutic Strategy for Treatment of Neurodegenerative Diseases

“…So far, a number of UPS regulators were developed. For example, cAMP phosphodiesterases inhibitors and UCHL1 that can modulate the brain cAMP-dependent protein kinase A (PKA)-cAMP response element binding protein (CREB) PKA-pCREB levels in AD subjects, resulting in enhanced protein degradation and synaptic functions (Cao et al, 2019). According to the collected data, a number of PPs are able to exert UPS inhibitory activity, mainly through chymotrypsin-like activity on both intracellular 26S and purified 20S proteasome.…”

Changes in endolysosomal organization define a pre-degenerative state in the crumbs mutant Drosophila retina

“…Therefore, it is not surprising that impaired trafficking, induced by aging, environmental factors or mutations in genes encoding important components involved in trafficking, is associated with numerous detrimental human diseases. These include neurodegenerative diseases in particular, characterized by the progressive loss of neuronal function, such as Alzheimer’s and Parkinson’s disease, or retinal degeneration, leading to blindness [1, 2]. Important insight into the regulation of intracellular trafficking has been obtained by studies in model organisms, notably the fruit fly Drosophila melanogaster .…”

Systemic Actions of SGLT2 Inhibition on Chronic mTOR Activation as a Shared Pathogenic Mechanism between Alzheimer’s Disease and Diabetes

“…One of AD's vulnerable brain regions is the hippocampus. It is here that different factors related to the endo-lysosomal and autophagy system have been reported: increased number of endosomal compartments, abnormal accumulation of autophagic vacuoles and altered expression levels of protein degradation key regulators [49]. Abnormal functions of the endo-lysosomal and autophagic networks are common in AD due to their implication in the homeostasis of Aβ and tau [50].…”