Apoptotic Pathways and Alzheimer’s Disease: Probing Therapeutic Potential

Sharma, Vivek; Singh, Thakur Gurjeet; Singh, Simranjeet; Garg, Nikhil; Dhiman, Sonia

doi:10.1007/s11064-021-03418-7

Cited by 98 publications

(56 citation statements)

References 161 publications

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“…Apoptosis has long been debated to be responsible for neuronal loss in AD [ 51 , 55 ], although previous post-mortem studies have shown morphological and molecular signs of apoptosis to be very rare, affecting only 0.02–0.1% of neurons [ 26 ]. In addition, some markers used to indicate apoptosis do not discriminate between necroptosis and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus

Jayaraman

Htike

James

et al. 2021

acta neuropathol commun

125

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The pathogenetic mechanisms underlying neuronal death and dysfunction in Alzheimer’s disease (AD) remain unclear. However, chronic neuroinflammation has been implicated in stimulating or exacerbating neuronal damage. The tumor necrosis factor (TNF) superfamily of cytokines are involved in many systemic chronic inflammatory and degenerative conditions and are amongst the key mediators of neuroinflammation. TNF binds to the TNFR1 and TNFR2 receptors to activate diverse cellular responses that can be either neuroprotective or neurodegenerative. In particular, TNF can induce programmed necrosis or necroptosis in an inflammatory environment. Although activation of necroptosis has recently been demonstrated in the AD brain, its significance in AD neuron loss and the role of TNF signaling is unclear. We demonstrate an increase in expression of multiple proteins in the TNF/TNF receptor-1-mediated necroptosis pathway in the AD post-mortem brain, as indicated by the phosphorylation of RIPK3 and MLKL, predominantly observed in the CA1 pyramidal neurons. The density of phosphoRIPK3 + and phosphoMLKL + neurons correlated inversely with total neuron density and showed significant sexual dimorphism within the AD cohort. In addition, apoptotic signaling was not significantly activated in the AD brain compared to the control brain. Exposure of human iPSC-derived glutamatergic neurons to TNF increased necroptotic cell death when apoptosis was inhibited, which was significantly reversed by small molecule inhibitors of RIPK1, RIPK3, and MLKL. In the post-mortem AD brain and in human iPSC neurons, in response to TNF, we show evidence of altered expression of proteins of the ESCRT III complex, which has been recently suggested as an antagonist of necroptosis and a possible mechanism by which cells can survive after necroptosis has been triggered. Taken together, our results suggest that neuronal loss in AD is due to TNF-mediated necroptosis rather than apoptosis, which is amenable to therapeutic intervention at several points in the signaling pathway.

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Section: Discussionmentioning

confidence: 99%

TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus

Jayaraman

Htike

James

et al. 2021

acta neuropathol commun

125

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“…Growing evidence have proved that Aβ triggers the chain events downstream in the pathological course of AD, including tau pathology. However, other processes such as neural inflammation ( Leng and Edison, 2021 ), oxidative stress ( Song et al, 2021 ), apoptosis ( Sharma et al, 2021 ), autophagy ( Zhang et al, 2021 ) and metal dysregulation ( Wang et al, 2020 ; Aaseth et al, 2021 ) are also found in AD pathology. Some of these processes are even involved in the deposition of Aβ.…”

Section: Introductionmentioning

confidence: 99%

Iron Dyshomeostasis and Ferroptosis: A New Alzheimer’s Disease Hypothesis?

Wang

Shen

et al. 2022

Front. Aging Neurosci.

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Iron plays a crucial role in many physiological processes of the human body, but iron is continuously deposited in the brain as we age. Early studies found iron overload is directly proportional to cognitive decline in Alzheimer’s disease (AD). Amyloid precursor protein (APP) and tau protein, both of which are related to the AD pathogenesis, are associated with brain iron metabolism. A variety of iron metabolism-related proteins have been found to be abnormally expressed in the brains of AD patients and mouse models, resulting in iron deposition and promoting AD progression. Amyloid β (Aβ) and hyperphosphorylated tau, two pathological hallmarks of AD, can also promote iron deposition in the brain, forming a vicious cycle of AD development-iron deposition. Iron deposition and the subsequent ferroptosis has been found to be a potential mechanism underlying neuronal loss in many neurodegenerative diseases. Iron chelators, antioxidants and hepcidin were found useful for treating AD, which represents an important direction for AD treatment research and drug development in the future. The review explored the deep connection between iron dysregulation and AD pathogenesis, discussed the potential of new hypothesis related to iron dyshomeostasis and ferroptosis, and summarized the therapeutics capable of targeting iron, with the expectation to draw more attention of iron dysregulation and corresponding drug development.

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“…36–40 Hyperactivated JAK/STAT pathway is involved in the imbalance of Th17/Tregs. 41 Both TGF-β1 and IL-10 could regulate the differentiation of Th17 cells and Foxp3 + Treg cells by affecting the JAK/STAT pathway, thereby affecting the balance of the Th17/Tregs axis. 42 Thus, it is feasible to study the effect of GLP-1 on alleviating cognitive impairment of CCH from regulating the imbalance of the Th17/Tregs axis in the future.…”

Section: Discussionmentioning

confidence: 99%

Polysaccharide from Ganoderma lucidum alleviates cognitive impairment in a mouse model of chronic cerebral hypoperfusion by regulating CD4⁺CD25⁺Foxp3⁺ regulatory T cells

Song

Wang

et al. 2022

Food Funct.

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Apoptotic Pathways and Alzheimer’s Disease: Probing Therapeutic Potential

Cited by 98 publications

References 161 publications

TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus

TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus

Iron Dyshomeostasis and Ferroptosis: A New Alzheimer’s Disease Hypothesis?

Polysaccharide from Ganoderma lucidum alleviates cognitive impairment in a mouse model of chronic cerebral hypoperfusion by regulating CD4⁺CD25⁺Foxp3⁺ regulatory T cells

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Apoptotic Pathways and Alzheimer’s Disease: Probing Therapeutic Potential

Cited by 98 publications

References 161 publications

TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus

TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus

Iron Dyshomeostasis and Ferroptosis: A New Alzheimer’s Disease Hypothesis?

Polysaccharide from Ganoderma lucidum alleviates cognitive impairment in a mouse model of chronic cerebral hypoperfusion by regulating CD4+CD25+Foxp3+ regulatory T cells

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Polysaccharide from Ganoderma lucidum alleviates cognitive impairment in a mouse model of chronic cerebral hypoperfusion by regulating CD4⁺CD25⁺Foxp3⁺ regulatory T cells