Role of autophagy in the pathogenesis of Alzheimer disease

Abstract

IntroductionAlzheimer disease (AD) is mainly characterized by progressive degeneration of the brain cells and leads to irreversible decline in cognitive abilities. The major pathological factor of this disorder is accumulation of amyloid-β (Aβ) protein in the cortex and hippocampal area, resulting in cognitive impairment and memory loss. Researches on therapeutic strategies for AD have mainly focused on anti-Aβ strategies, but most recently, studies examining the effect of monoclonal antibodies against Aβ protein such as solanezumab and bapineuzumab have resulted in disappointment due to high toxicity or ineffectiveness (1,2).Autophagy is thought to be one of the cleaving systems clearing toxic Aβ proteins from neurons. This pathway sustains cell life by protecting cells against deprivation and other threatening stressors (3). Another hallmark pathological process in AD is accumulation of hyperphosphorylated tau protein in the brain, resulting in neurofibrillary tangles. Autophagy is an inhibitor of the mammalian target of rapamycin (mTOR) induction pathway, which has been shown to be a promoter of hyperphosphorylation and accumulation of tau proteins (4).There is growing clinical and preclinical evidence about association of autophagy and AD in the literature, but none of these studies have succeeded in showing a link between autophagy and modulation of the disease progression yet (5). In this review, the importance of autophagy in AD pathogenesis will be discussed in light of the current knowledge in the literature. Definition and mechanisms of autophagyAutophagy is a process of self-digestion. It is thought to be a response to stressors and it allows cells to adapt to environmental changes (6). Deprivations in cell conditions may cause induction of autophagy to provide energy for the synthesis of essential substrates that are important for survival of organelles and cells (7). Since de Duve first described autophagy in 1963, our knowledge about this issue has continued to grow, especially in the last decade (6). Today it is thought that there is an association between autophagy and some disorders like cancer, infectious disease, and neurodegenerative disorders (8).Sequestration in the autophagy process first begins with the formation of a phagophore (Figure) (9). It then expands into a double-membrane autophagosome and surrounds a portion of the cytoplasm (6). Endosome, the product of endocytosis, fuses with the autophagosome, and this new product is called an amphisome (6). The autophagosome or amphisome fuses with a lysosome Abstract: Alzheimer disease (AD) is the most common progressive neurodegenerative disorder causing increased morbidity and mortality. It is characterized by accumulation of amyloid-β in neurons. As there is no known definitive treatment of this disorder, studies trying to determine its exact pathogenetic pathways and target therapies for these specific pathways are being rapidly conducted. Autophagy is one of the areas of interest in studies on the pathogenesis of AD. It is a process of ...

Iron Deposition Leads to Neuronal α-Synuclein Pathology by Inducing Autophagy Dysfunction

“…Excessive activation of autophagy is considered pernicious and has been determined to contribute to neuronal death (42). The disruption of autophagy is also harmful, resulting in the accumulation of misfolded proteins and dysfunctional organelles in cells (43, 44). The coordination of autophagic functions, including activation and inhibition, ensures the balance between cell growth and death.…”

Basal ryanodine receptor activity suppresses autophagic flux

“…During AD, lysosomal functioning is hampered, resulting in a reduced clearance of autophagosomal cargo at the lysosomes. (45,46) At the same time, increased levels of RyR3 as well as excessive RyR-mediated Ca 2+ release have been shown to be early/intermediate events in AD pathogenesis in several models. (19,(23)(24)(25)47) Blocking RyRs utilizing dantrolene has been reported to have beneficial effects in these mouse models by reducing pathological protein aggregates and memory impairment.…”

Exosome-Shuttled circSHOC2 from IPASs Regulates Neuronal Autophagy and Ameliorates Ischemic Brain Injury via the miR-7670-3p/SIRT1 Axis

“… 30 Recently, autophagy has been recognized as a key process in ischemic stroke, in addition to neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. 31 , 32 It is principally thought that autophagy plays an important role in protecting neurons from inflammation. Recent evidence has also demonstrated an important role of autophagy in ischemic stroke.…”