Chapter 19. Targeted Protein Degradation as a Therapeutic Avenue for Alzheimer's Disease

2022 ◽  
pp. 552-577
Author(s):  
Tanmay Mondal ◽  
Bhubaneswar Mandal
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Degradation ◽  
Therapeutic Avenue

The role of ubiquitin proteasomal system and autophagy-lysosome pathway in Alzheimer’s disease

2017 ◽  
Vol 28 (8) ◽  
Author(s):  
Yuan Zhang ◽  
Xu Chen ◽  
Yanfang Zhao ◽  
Murugavel Ponnusamy ◽  
Ying Liu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Degradation ◽  
Molecular Chaperones ◽  
Elderly Population ◽  
Neurodegenerative Disorder ◽  
The Elderly ◽  
Pathological Process ◽  
Β Amyloid

AbstractAlzheimer’s disease (AD) is the most common neurodegenerative disorder leading to dementia in the elderly population. AD is associated with the buildup of β-amyloid and tau, which aggregate into extracellular plaques and neurofibrillary tangles. Although the exact mechanism of pathological process of AD is unclear, the dysfunction of protein degradation mechanisms has been proposed to play an important role in AD. The cellular degradation of abnormal or misfolded proteins consists of three different mechanisms: the ubiquitin proteasomal system (UPS), autophagy-lysosomal pathway (ALP), and interaction of molecular chaperones with UPS or ALP. Any disturbance to these systems causes proteins to accumulate, resulting in pathological process of AD. In this review, we summarize the knowledge of protein degradation pathways in the pathogenesis of AD in light of the current literature. In the future, the regulation UPS or ALP machineries could be the cornerstones of the treatment of AD.

Immunolocalization of Tom1 in relation to protein degradation systems in Alzheimer's disease

2016 ◽  
Vol 365 ◽  
pp. 101-107 ◽  
Author(s):  
Kouki Makioka ◽  
Tsuneo Yamazaki ◽  
Masamitsu Takatama ◽  
Masaki Ikeda ◽  
Shigeo Murayama ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Degradation

scholarly journals Rivastigmine attenuates the Alzheimer's disease related protein degradation and apoptotic neuronal death signaling

2021 ◽  
Author(s):  
Parul Gupta ◽  
Shubhangini Tiwari ◽  
Abhishek Singh ◽  
Amit Pal ◽  
Amit Mishra ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Aggregation ◽  
Er Stress ◽  
Protein Degradation ◽  
Acetylcholinesterase Activity ◽  
Inhibitory Effect ◽  
Proteasome Activity ◽  
Amyloid Aggregation ◽  
Biochemical Alterations

Rivastigmine is clinical drug for patients of Alzheimer’s disease (AD) exerting its inhibitory effect on acetylcholinesterase activity however, its effect on other disease related pathological mechanisms are not yet known. This study was conducted to evaluate the effect of rivastigmine on protein aggregation and degradation related mechanisms employing streptozotocin (STZ) induced experimental rat model. The known inhibitory effect of rivastigmine on cognition and acetylcholinesterase activity was observed in both cortex and hippocampus and further its effect on tau level, amyloid aggregation, biochemical alterations, endoplasmic reticulum (ER) stress, calcium homeostasis, proteasome activity and apoptosis was estimated. STZ administration in rat brain caused significant cognitive impairment, augmented acetylcholinesterase activity, tau phosphorylation and amyloid aggregation which were significantly inhibited with rivastigmine treatment. STZ also caused significant biochemical alterations which were attenuated with rivastigmine treatment. Since AD pathology is related to protein aggregation and we have found disease related amyloid aggregation, further the investigation was done to decipher the ER functionality and apoptotic signalling. STZ caused significantly altered level of ER stress related markers (GRP78, GADD153 and caspase-12) which were significantly inhibited with rivastigmine treatment. Further the effect of rivastigmine was estimated on proteasome activity in both regions. Rivastigmine treatment significantly enhances the proteasome activity and may contributes in removal of amyloid aggregation. In conclusion, findings suggested that along with inhibitory effect of rivastigmine on acetylcholinesterase activity and up to some extent on cognition, it has significant effect on disease related biochemical alterations, ER functionality, protein degradation machinery and neuronal apoptosis.

scholarly journals Astrocytes in depression and Alzheimer’s disease

2021 ◽  
Author(s):  
Yang Liao ◽  
Qu Xing ◽  
Qianqian Li ◽  
Jing Zhang ◽  
Ruiyuan Pan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Critical Role ◽  
Brain Diseases ◽  
Human Society ◽  
Loss Of Self ◽  
Correlational Research ◽  
Gradual Loss ◽  
The Central Nervous System ◽  
Therapeutic Avenue

AbstractAstrocytes are an abundant subgroup of cells in the central nervous system (CNS) that play a critical role in controlling neuronal circuits involved in emotion, learning, and memory. In clinical cases, multiple chronic brain diseases may cause psychosocial and cognitive impairment, such as depression and Alzheimer’s disease (AD). For years, complex pathological conditions driven by depression and AD have been widely perceived to contribute to a high risk of disability, resulting in gradual loss of self-care ability, lower life qualities, and vast burden on human society. Interestingly, correlational research on depression and AD has shown that depression might be a prodrome of progressive degenerative neurological disease. As a kind of multifunctional glial cell in the CNS, astrocytes maintain physiological function via supporting neuronal cells, modulating pathologic niche, and regulating energy metabolism. Mounting evidence has shown that astrocytic dysfunction is involved in the progression of depression and AD. We herein review the current findings on the roles and mechanisms of astrocytes in the development of depression and AD, with an implication of potential therapeutic avenue for these diseases by targeting astrocytes.

scholarly journals Interplay Between Oxidative Damage, Protein Synthesis, and Protein Degradation in Alzheimer's Disease

2006 ◽  
Vol 2006 ◽  
pp. 1-3 ◽  
Author(s):  
Jeffrey N. Keller
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Synthesis ◽  
Steady State ◽  
Oxidative Damage ◽  
Cell Viability ◽  
Protein Degradation ◽  
Cellular Processes ◽  
Damage Protein

Protein synthesis and protein degradation are highly regulated cellular processes that are essential to maintaining cell viability. Numerous studies now indicate that protein synthesis and protein degradation are significantly altered in Alzheimer's disease (AD), with impairments in these two processes potentially contributing to AD pathogenesis. Alterations in steady state protein regulation may be a particularly important factor in regulating whether cells maintain homeostasis in response to oxidative damage, or conversely whether oxidative stress is induced by oxidative damage. The focus of this review is to discuss recent findings on each of these topics, and to discuss their importance to the onset and progression of AD.

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