Autophagy in Alzheimer’s disease

Zare-Shahabadi, Ameneh; Masliah, Eliezer; Johnson, Gail V.W.; Rezaei, Nima

doi:10.1515/revneuro-2014-0076

Cited by 185 publications

(151 citation statements)

References 114 publications

(153 reference statements)

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“…Multiple researchers have verified that increased activity of the autophagy pathway leads to increased degradation of the tau protein and hence reduced intracellular tau aggregation [53]. Nevertheless, the molecular interaction between autophagy and Aβ remains controversial.…”

Section: Major Cancer-related Signaling Pathways With Links To Ad mentioning

confidence: 99%

Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology

Guo

Cheng²,

North

2017

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Alzheimer’s disease (AD) is an aging-related neurodegenerative disease and accounts for majority of human dementia. The hyper-phosphorylated tau-mediated intracellular neurofibrillary tangle and amyloid β-mediated extracellular senile plaque are characterized as major pathological lesions of AD. Different from the dysregulated growth control and ample genetic mutations associated with human cancers, AD displays damage and death of brain neurons in the absence of genomic alterations. Although various biological processes predominately governing tumorigenesis such as inflammation, metabolic alteration, oxidative stress and insulin resistance have been associated with AD genesis, the mechanistic connection of these biological processes and signaling pathways including mTOR, MAPK, SIRT, HIF, and the FOXO pathway controlling aging and the pathological lesions of AD are not well recapitulated. Hence, we performed a thorough review by summarizing the physiological roles of these key cancer-related signaling pathways in AD pathogenesis, comprising of the crosstalk of these pathways with neurofibrillary tangle and senile plaque formation to impact AD phenotypes. Importantly, the pharmaceutical investigations of anti-aging and AD relevant medications have also been highlighted. In summary, in this review, we discuss the potential role that cancer-related signaling pathways may play in governing the pathogenesis of AD, as well as their potential as future targeted strategies to delay or prevent aging-related diseases and combating AD.

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Section: Major Cancer-related Signaling Pathways With Links To Ad mentioning

confidence: 99%

Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology

Guo

Cheng²,

North

2017

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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“…These observations may be significant in terms of differentiating AD from normal ageing, as there is copious evidence that the autophagic process is downregulated in normal ageing [288,289]. However, despite the transcriptional upregulation of autophagy seen in AD patients, the weight of evidence indicates that autophagic lysosomal clearance is dysregulated and defective in the hippocampus of AD patients, even in those in the very early stages of their disease [287] [24].…”

Section: Oxidative Stress Mtor Activation and Impaired Autophagy And mentioning

confidence: 99%

“…Other commonly reported abnormalities include compromised autophagy and lysosomal clearance accompanied by elevated activity of both glycogen synthase kinase-3 (GSK-3) and mechanistic (previously mammalian) target of rapamycin (mTOR), coupled with a defective ubiquitin-proteasome system (UPS) [12,[23][24][25][26][27]. Several authors have also reported abnormalities in the activity of several kinases and phosphatases, most notably mitogen-activated protein kinases (MAPKs) and protein phosphatase 2A (PP2A or PP2), and transition metal dyshomeostasis, which could all arguably play a role, either as primary or secondary drivers of disease activity [11-13, 16, 28-30].…”

Section: Introductionmentioning

confidence: 99%

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

et al. 2018

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The classical amyloid cascade model for Alzheimer's disease (AD) has been challenged by several findings. Here, an alternative molecular neurobiological model is proposed. It is shown that the presence of the APOE ε4 allele, altered miRNA expression and epigenetic dysregulation in the promoter region and exon 1 of TREM2, as well as ANK1 hypermethylation and altered levels of histone post-translational methylation leading to increased transcription of TNFA, could variously explain increased levels of peripheral and central inflammation found in AD. In particular, as a result of increased activity of triggering receptor expressed on myeloid cells 2 (TREM-2), the presence of the apolipoprotein E4 (ApoE4) isoform, and changes in ANK1 expression, with subsequent changes in miR-486 leading to altered levels of protein kinase B (Akt), mechanistic (previously mammalian) target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3), all of which play major roles in microglial activation, proliferation and survival, there is activation of microglia, leading to the subsequent (further) production of cytokines, chemokines, nitric oxide, prostaglandins, reactive oxygen species, inducible nitric oxide synthase and cyclooxygenase-2, and other mediators of inflammation and neurotoxicity. These changes are associated with the development of amyloid and tau pathology, mitochondrial dysfunction (including impaired activity of the electron transport chain, depleted basal mitochondrial potential and oxidative damage to key tricarboxylic acid enzymes), synaptic dysfunction, altered glycogen synthase kinase-3 (GSK-3) activity, mTOR activation, impairment of autophagy, compromised ubiquitin-proteasome system, iron dyshomeostasis, changes in APP translation, amyloid plaque formation, tau hyperphosphorylation and neurofibrillary tangle formation.

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“…Autophagy negatively regulates inflammation. Increased activity of the autophagy pathway leads to increased degradation of the tau protein and hence reduced intracellular tau aggregation [49], suggesting that the aberrant accumulation of tau proteins may, at least in part, be due to impaired autophagy inside neurons [54]. Another major protective role of autophagy is the elimination of abnormal mitochondria, a source of oxidative stress.…”

Section: Autophagy In Ad Genesismentioning

confidence: 99%

“…Evidence is presented suggesting amyloid oligomers as necessary but insufficient causes of the dementia and that, for dementia to develop, additional cofactors are required [13]. Those cofactors include several subcellular processes including oxidative damage [10,[14][15][16][17][18][19][20][21][22][23], recruitment of peripheral immune cells and excessive production of pro-inflammatory mediators [10,[24][25][26][27][28][29], mitochondrial impairments and chronic energy imbalance [12,20,[30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47], chronic endoplasmic reticulum (ER) stress [48] and autophagy dysfunction [22,[49][50][51][52][53][54], the abnormality and dysfunction of MAM (the mitocho...…”

Section: Introductionmentioning

confidence: 99%