Tau hyperphosphorylation induces apoptotic escape and triggers neurodegeneration in Alzheimer’s disease

Wang, Jian‐Zhi; Wang, Zhi-Hao; Tian, Qing

doi:10.1007/s12264-013-1415-y

Cited by 63 publications

(42 citation statements)

References 60 publications

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“…The production and maturation of BDNF in the brain is regulated by Cu 2+ -dependent metalloproteinases. In SHSY5Y cells, Cu 2+ treatment decreased pro-BDNF level in cells and increased pro-and mature BDNF levels in the medium [128] with a strong decrease of the proliferative activity of both cleaved BDNF (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) and the full length protein [129]. Application of zinc chelator induced reduction of BDNF level, synaptic plasticity-related proteins and dendritic spine density in vivo, which further confirm that appropriate amount of Zn 2+ is essential in brain development and the synaptic functions [130].…”

Section: Zincmentioning

confidence: 54%

“…[5][6][7]. Recent studies suggest that tau hyperphosphorylation may play a dual role in AD neurodegeneration, i.e., tau hyperphosphorylation renders the cells more resistant to acute apoptosis [8][9][10][11][12], while the increasing intracellular tau accumulation induces multiple cellular impairments, including endoplasmic reticulum (ER) stress, deficits of mitophagy and autophagy, deficits of synaptic transmission, etc., and eventually leads to a chronic neurodegeneration [5,13,14].…”

Section: Introductionmentioning

confidence: 99%

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Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Wang

Yin

Liu

et al. 2020

Transl Neurodegener

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296

188

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Background: The homeostasis of metal ions, such as iron, copper, zinc and calcium, in the brain is crucial for maintaining normal physiological functions. Studies have shown that imbalance of these metal ions in the brain is closely related to the onset and progression of Alzheimer's disease (AD), the most common neurodegenerative disorder in the elderly. Main body: Erroneous deposition/distribution of the metal ions in different brain regions induces oxidative stress. The metal ions imbalance and oxidative stress together or independently promote amyloid-β (Aβ) overproduction by activating βor γ-secretases and inhibiting α-secretase, it also causes tau hyperphosphorylation by activating protein kinases, such as glycogen synthase kinase-3β (GSK-3β), cyclin-dependent protein kinase-5 (CDK5), mitogenactivated protein kinases (MAPKs), etc., and inhibiting protein phosphatase 2A (PP2A). The metal ions imbalances can also directly or indirectly disrupt organelles, causing endoplasmic reticulum (ER) stress; mitochondrial and autophagic dysfunctions, which can cause or aggravate Aβ and tau aggregation/accumulation, and impair synaptic functions. Even worse, the metal ions imbalance-induced alterations can reversely exacerbate metal ions misdistribution and deposition. The vicious cycles between metal ions imbalances and Aβ/tau abnormalities will eventually lead to a chronic neurodegeneration and cognitive deficits, such as seen in AD patients. Conclusion: The metal ions imbalance induces Aβ and tau pathologies by directly or indirectly affecting multiple cellular/ subcellular pathways, and the disrupted homeostasis can reversely aggravate the abnormalities of metal ions transportation/ deposition. Therefore, adjusting metal balance by supplementing or chelating the metal ions may be potential in ameliorating AD pathologies, which provides new research directions for AD treatment.

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Section: Zincmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Wang

Yin

Liu

et al. 2020

Transl Neurodegener

Self Cite

296

188

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“…A lot of evidence supports the toxic effects of tau hyperphosphorylation including disrupts microtubule dynamics, promotes tangle formation, and inhibits proteasome activity (61)(62)(63). Some recent studies suggest that tau hyperphosphorylation renders the cells more resistant to the acute apoptosis (64). That seems to say the neuroprotective role of tau hyperphosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Metformin treatment improves the spatial memory of aged mice in an APOE genotype–dependent manner

et al. 2019

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Aging and apolipoprotein E4 (ApoE4) can increase the risk of cognitive impairment and neurodegenerative disorders, including Alzheimer's disease (AD), and patients with type 2 diabetes mellitus are highly susceptible to cognitive dysfunction. Recent research has indicated that metformin, a prescribed drug for type 2 diabetes, may affect cognitive function; however, findings regarding its efficacy are largely controversial. The current study reported that a 5‐mo metformin administration (300 mg/kg/d) starting at 13 mo old improved the spatial memory of ApoE3‐target replacement (TR) mice, not ApoE4‐TR mice. It found that in aged ApoE3‐TR mice, metformin treatment, at a molecular level, inhibited AMPK activity, increased insulin signaling, and activated mammalian target of rapamycin signaling, resulting in an enhanced expression of postsynaptic proteins; but the response of the neuronal AMPK activity and insulin signaling to metformin was blunt in aged ApoE4‐TR mice. Meanwhile, metformin treatment also increased the phosphorylation of tau in both ApoE3‐TR and ApoE4‐TR mice, implying that metformin may have side effects in human. These findings suggest that metformin can improve the cognitive performance of aged mice in an APOE genotype–dependent manner, which provides empirical insights into the clinical value of metformin for ApoE4‐ and age‐related AD prevention and treatment.—Zhang, J., Lin, Y., Dai, X., Fang, W., Wu, X., Chen, X. Metformin treatment improves the spatial memory of aged mice in an APOE genotype–dependent manner. FASEB J. 33, 7748–7757 (2019). http://www.fasebj.org

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“…The disease is marked histopathologically by extracellular deposit of amyloid beta (Aβ) surrounded by dystrophic neuritis forming senile plaques (SPs), and intracellular hyperphosphorylated τ made neurofibrillary tangles (NFTs) . The Aβ peptides are the result of proteolysis of the amyloid precursor protein (APP) by two proteases, the beta APP cleaving enzyme 1 (BACE1), also called β‐secretase, and the γ‐secretase, and the hyperphosphorylated τ protein in the NFTs results from the dysregulation of kinase/phosphatase system, involving mainly glycogen synthase kinase 3β (GSK3β) and protein phosphatase 2A (PP2A) among other . Other key players in AD pathogenesis include oxidative stress seen as lipids; proteins and nucleic acid oxidations, neuroinflammation, calcium homeostasis disturbance.…”

Section: Introductionmentioning

confidence: 99%

Involvement of calpain in the neuropathogenesis of Alzheimer’s disease

Mahaman

Huang

Afewerky

et al. 2018

Medicinal Research Reviews

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Alzheimer's disease (AD) is the most common (60% to 80%) age-related disease associated with dementia and is characterized by a deterioration of behavioral and cognitive capacities leading to death in few years after diagnosis, mainly due to complications from chronic illness. The characteristic hallmarks of the disease are extracellular senile plaques (SPs) and intracellular neurofibrillary tangles (NFTs) with neuropil threads, which are a direct result of amyloid precursor protein (APP) processing to Aβ, and τ hyperphosphorylation. However, many indirect underlying processes play a role in this event. One of these underlying mechanisms leading to these histological hallmarks is the uncontrolled hyperactivation of a family of cysteine proteases called calpains. Under normal physiological condition calpains participate in many processes of cells' life and their activation is tightly controlled. However, with an increase in age, increased oxidative stress and other excitotoxicity assaults, this regulatory system becomes impaired and result in increased activation of these proteases involving them in the pathogenesis of various diseases including neurodegeneration like AD. Reviewed here is a pool of data on the implication of calpains in the pathogenesis of AD, the underlying molecular mechanism, and the potential of targeting these enzymes for AD therapeutics.

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Tau hyperphosphorylation induces apoptotic escape and triggers neurodegeneration in Alzheimer’s disease

Cited by 63 publications

References 60 publications

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Metformin treatment improves the spatial memory of aged mice in an APOE genotype–dependent manner

Involvement of calpain in the neuropathogenesis of Alzheimer’s disease

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