Mitophagy enhancers against phosphorylated Tau-induced mitochondrial and synaptic toxicities in Alzheimer disease

Kshirsagar, Sudhir; Sawant, Neha; Morton, Hallie; Reddy, Arubala P.; Reddy, P. Hemachandra

doi:10.1016/j.phrs.2021.105973

Cited by 42 publications

(28 citation statements)

References 49 publications

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“…In addition, Kondo et al showed that an anti-cis p-tau-specific antibody could rescue the majority of cistauosis-induced consequences, including apoptosis and mitochondrial dysfunction [ 109 ]. The concept that tau pathology is linked to mitochondrial dysregulation has been endorsed by studies from the field of Alzheimer’s research [ 110 , 111 , 112 , 113 ]. Kondo et al’s findings and the possible use of a p-tau therapeutic antibody were subsequently supported by a number of recent studies [ 114 , 115 , 116 ].…”

Section: Emerging Treatmentsmentioning

confidence: 99%

Secondary Mechanisms of Neurotrauma: A Closer Look at the Evidence

et al. 2022

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Traumatic central nervous system injury is a leading cause of neurological injury worldwide. While initial neuroresuscitative efforts are focused on ameliorating the effects of primary injury through patient stabilization, secondary injury in neurotrauma is a potential cause of cell death, oxidative stress, and neuroinflammation. These secondary injuries lack defined therapy. The major causes of secondary injury in neurotrauma include endoplasmic reticular stress, mitochondrial dysfunction, and the buildup of reactive oxygen or nitrogenous species. Stress to the endoplasmic reticulum in neurotrauma results in the overactivation of the unfolded protein response with subsequent cell apoptosis. Mitochondrial dysfunction can lead to the release of caspases and the buildup of reactive oxygen species; several characteristics make the central nervous system particularly susceptible to oxidative damage. Together, endoplasmic reticulum, mitochondrial, and oxidative stress can have detrimental consequences, beginning moments and lasting days to months after the primary injury. Understanding these causative pathways has led to the proposal of various potential treatment options.

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Section: Emerging Treatmentsmentioning

confidence: 99%

Secondary Mechanisms of Neurotrauma: A Closer Look at the Evidence

et al. 2022

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“…Amelioration of memory deficits, reduction in cognitive impairment and improvement in spatial memory are common effects observed in AD-induced mouse models that consumed Uro-A-enriched diets [ 108 ]. The molecular mechanisms associated with these benefits include reduction in Aβ-plaque deposition and tau phosphorylation, APP down-regulation, autophagy induction, and attenuation of glial cell activation and inflammation (lower levels of pro-inflammatory cytokines and inhibition of NF-κB pathway activation) [ 108 , 124 , 125 , 126 ]. Equol is in the spotlight as a possible protective factor against cognitive impairment [ 127 , 128 ].…”

Section: Modifiable Proinflammatory Lipid Mediators In Admentioning

confidence: 99%

Modifiable Innate Biology within the Gut–Brain Axis for Alzheimer’s Disease

et al. 2022

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Alzheimer’s disease (AD) is a prototypical inflammation-associated loss of cognitive function, with approximately 90% of the AD burden associated with invading myeloid cells controlling the function of the resident microglia. This indicates that the immune microenvironment has a pivotal role in the pathogenesis of the disease. Multiple peripheral stimuli, conditioned by complex and varied interactions between signals that stem at the intestinal level and neuroimmune processes, are involved in the progression and severity of AD. Conceivably, the targeting of critical innate immune signals and cells is achievable, influencing immune and metabolic health within the gut–brain axis. Considerable progress has been made, modulating many different metabolic and immune alterations that can drive AD development. However, non-pharmacological strategies targeting immunometabolic processes affecting neuroinflammation in AD treatment remain general and, at this point, are applied to all patients regardless of disease features. Despite these possibilities, improved knowledge of the relative contribution of the different innate immune cells and molecules comprising the chronically inflamed brain network to AD pathogenesis, and elucidation of the network hierarchy, are needed for planning potent preventive and/or therapeutic interventions. Moreover, an integrative perspective addressing transdisciplinary fields can significantly contribute to molecular pathological epidemiology, improving the health and quality of life of AD patients. This review is intended to gather modifiable immunometabolic processes based on their importance in the prevention and management of AD.

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“…Defective mitophagy is an emerging science and is caused by impaired mitochondrial dynamics (increased fission, decreased fusion or vice versa), defective mitochondrial biogenesis and abnormal interaction of mutant proteins such as Aβ and p-Tau with mitochondrial proteins Drp1, VDAC1, CypD, ABAD and others [ 18 , 19 , 20 , 21 , 22 ]. Recent evidence from our lab and others indicates that mitophagy proteins PINK1 and Parkin are largely reduced in AD, primarily due to abnormal interactions between Aβ and p-Tau with the fission protein Drp1 [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ], leading to reduced clearance of dead or dying mitochondria. These studies also suggest that reduced levels of Drp1, VDAC1, CypD and ABAD may inhibit abnormal interactions with Aβ and p-tau and maintain the quality of mitochondria, mitochondrial health and mitophagy in AD [ 5 , 31 ].…”

Section: Introductionmentioning

confidence: 99%

“…Ellagic acid is transformed by the gut microbiota into urolithins. Recent in vitro studies have investigated urolithins’ antioxidant effects, particularly on aging and age-related neurodegenerative diseases, such as AD [ 28 , 29 , 30 , 31 , 32 , 33 ]. Recent familial AD mouse models revealed that urolithin A ameliorated cognitive impairment, prevented neuronal apoptosis and enhanced neurogenesis in APP/PS1 mice.…”

Section: Introductionmentioning

confidence: 99%

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A Combination Therapy of Urolithin A+EGCG Has Stronger Protective Effects than Single Drug Urolithin A in a Humanized Amyloid Beta Knockin Mice for Late-Onset Alzheimer’s Disease

Kshirsagar

Alvir

Pradeepkiran

et al. 2022

Cells

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In the current study, for the first time, we study mitophagy enhancer urolithin A and a combination of urolithin A+green tea extract EGCG against human Aβ peptide-induced mitochondrial and synaptic, dendritic, inflammatory toxicities and behavioral changes in humanized homozygous amyloid beta knockin (hAbKI) mice of late-onset Alzheimer’s disease (AD). Our findings reveal significantly increased positive effects of urolithin A and a combination treatment of urolithin A+EGCG in hAbKI mice for phenotypic behavioral changes including motor coordination, locomotion/exploratory activity, spatial learning and working memory. mRNA and protein levels of mitochondrial fusion, synaptic, mitophagy and autophagy genes were upregulated, and mitochondrial fission genes are downregulated in urolithin A and combine treatment in hAbKI mice; however, the effect is stronger in combined treatment. Immunofluorescence analysis of hippocampal brain sections shows similar findings of mRNA and protein levels. Mitochondrial dysfunction is significantly reduced in both treatment groups, but a stronger reduction is observed in combined treatment. Dendritic spines and lengths are significantly increased in both treatment groups, but the effect is stronger in combined treatment. The fragmented number of mitochondria is reduced, and mitochondrial length is increased, and mitophagosomal formations are increased in both the groups, but the effect is stronger in the combined treatment. The levels of amyloid beta (Aβ) 40 and Aβ42 are reduced in both treatments, however, the reduction is higher for combined treatment. These observations suggest that urolithin A is protective against human Aβ peptide-induced toxicities; however, combined treatment of urolithin A+EGCG is effective and stronger, indicating that combined therapy is promising to treat late-onset AD patients.

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Mitophagy enhancers against phosphorylated Tau-induced mitochondrial and synaptic toxicities in Alzheimer disease

Cited by 42 publications

References 49 publications

Secondary Mechanisms of Neurotrauma: A Closer Look at the Evidence

Secondary Mechanisms of Neurotrauma: A Closer Look at the Evidence

Modifiable Innate Biology within the Gut–Brain Axis for Alzheimer’s Disease

A Combination Therapy of Urolithin A+EGCG Has Stronger Protective Effects than Single Drug Urolithin A in a Humanized Amyloid Beta Knockin Mice for Late-Onset Alzheimer’s Disease

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