A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic Tau mouse model of Alzheimer disease

Abstract

The purpose of our study is to understand the impact of a partial dynamin-related protein 1 (Drp1) on cognitive behavior, mitophagy, autophagy and mitochondrial and synaptic activities in transgenic Tau mice in Alzheimer’s disease (AD). Our laboratory reported increased levels of amyloid-beta (Aβ) and phosphorylated Tau (P-Tau) and reported that abnormal interactions between Aβ and Drp1, P-Tau and Drp1 induced increased mitochondrial fragmentation and reduced fusion and synaptic activities in AD. These abnormal interactions result in the proliferation of dysfunctional mitochondria in AD neurons. Recent research on mitochondria revealed that fission protein Drp1 is largely implicated in mitochondrial dynamics in AD. To determine the impact of reduced Drp1 in AD, we recently crossed transgenic Tau mice with Drp1 heterozygote knockout (Drp1+/−) mice and generated double mutant (P301LDrp1+/−) mice. In the current study, we assessed the cognitive behavior, mRNA and protein levels of mitophagy, autophagy, mitochondrial biogenesis, dynamics and synaptic genes, mitochondrial morphology and mitochondrial function and dendritic spines in Tau mice relative to double mutant mice. When compared with Tau mice, double mutant mice did better on the Morris Maze (reduced latency to find hidden platform, increased swimming speed and time spent on quadrant) and rotarod (stayed a longer period of time) tests. Both mRNA- and protein-level autophagy, mitophagy, mitochondrial biogenesis and synaptic proteins were increased in double mutant mice compared with Tau (P301L) mice. Dendritic spines were significantly increased; mitochondrial number was reduced and length was increased in double mutant mice. Based on these observations, we conclude that reduced Drp1 is beneficial in a symptomatic-transgenic Tau (P301L) mice.

A Review of ApoE4 Interference Targeting Mitophagy Molecular Pathways for Alzheimer's Disease

“…Mitochondria fission is a basic and vital process via programmed and sequential membrane movement that (Mahaman et al, 2022 ) involves healthy mitochondria fragments for growing physiological requirements; (2020) aged or damaged mitochondria divided into healthy mitochondria for recycling and pre-degraded mitochondria for clearance (Wolf et al, 2020 ; Luan et al, 2021 ). Impaired mitochondrial dynamics is widely established in AD model mice and cells, as well as AD individuals (Manczak et al, 2011 ; Reddy et al, 2011 , 2018 ; Manczak and Reddy, 2012a ; Zhu et al, 2013 ; Kandimalla et al, 2021 ), as determined by the lower expression of mitochondrial fission genes ( DRP1 and FIS1 ) and higher phosphorylation level of dynamin-related protein1 (DRP1), leading to reductive mitochondria fragmentation and neuronal energy dysfunction (Reddy et al, 2011 ; Manczak and Reddy, 2012a ; Misrani et al, 2021 ; Wang et al, 2021a ; Dhapola et al, 2022 ). Incidentally, additional studies indicate that decreased DRP1 promotes cognitive performance and improves mitophagy and dendritic spines in tau-transgenic mouse model and APP/PS1 mice (Kandimalla et al, 2021 ; Misrani et al, 2021 ; Song et al, 2021 ), in which DRP1 is overactivated under abnormal conditions; and consistently, various DRP1 inhibitors promote fusion and improve cognition in AD (Dhapola et al, 2022 ).…”

“…Impaired mitochondrial dynamics is widely established in AD model mice and cells, as well as AD individuals (Manczak et al, 2011 ; Reddy et al, 2011 , 2018 ; Manczak and Reddy, 2012a ; Zhu et al, 2013 ; Kandimalla et al, 2021 ), as determined by the lower expression of mitochondrial fission genes ( DRP1 and FIS1 ) and higher phosphorylation level of dynamin-related protein1 (DRP1), leading to reductive mitochondria fragmentation and neuronal energy dysfunction (Reddy et al, 2011 ; Manczak and Reddy, 2012a ; Misrani et al, 2021 ; Wang et al, 2021a ; Dhapola et al, 2022 ). Incidentally, additional studies indicate that decreased DRP1 promotes cognitive performance and improves mitophagy and dendritic spines in tau-transgenic mouse model and APP/PS1 mice (Kandimalla et al, 2021 ; Misrani et al, 2021 ; Song et al, 2021 ), in which DRP1 is overactivated under abnormal conditions; and consistently, various DRP1 inhibitors promote fusion and improve cognition in AD (Dhapola et al, 2022 ). These suggest that correcting DRP1 activity might confer tolerance to cytotoxicity from p-Tau and Aβ (Manczak and Reddy, 2012a ; Kuruva et al, 2017 ; Reddy and Oliver, 2019 ) and there is a need for further investigation into the identified regulation underlying AD events.…”

“…Since SIRT1-involved neuroprotection plays extensive and multiple roles in AD progression (Fujita and Yamashita, 2018 ; Gomes et al, 2018 ), it might be helpful to extract the relationship between SIRT1 and ApoE4 and the potential mechanisms. Second, the abnormal interactions between DRP1 and hyperphosphorylated Tau, as well as DRP1 and Aβ monomers and oligomers, are established by coimmunoprecipitation (co-IP) and double-labeling immunofluorescence analysis, in postmortem brain tissues of AD patients and brain homogenates from several AD mouse models (Manczak et al, 2011 ; Reddy et al, 2011 ; Manczak and Reddy, 2012a ; Abtahi et al, 2020 ; Kandimalla et al, 2021 ), which is speculated that excessive p-Tau and Aβ accumulation may synergistically disrupt mitochondrial fragmentation in a ApoE4-dose-dependent manner. These findings may help to shed new light on the alternative link between ApoE4 and mitophagic dynamics.…”

“…Moreover, certain factors play multiple roles in mitochondria metabolism. SIRT1 (Lee et al, 2008 ; Jang et al, 2012 ; Lu et al, 2014 ; Ou et al, 2014 ; Qiao et al, 2018 ; Yao et al, 2021 ), Ca 2+ (Cereghetti et al, 2008 ; Ishihara et al, 2017 ; Barazzuol et al, 2020 ), Aβ (Manczak et al, 2011 ; Cai and Tammineni, 2016 ; Kerr et al, 2017 ; Reddy and Oliver, 2019 ), and Tau (Manczak and Reddy, 2012a ; Abtahi et al, 2020 ; Goudarzi et al, 2021 ; Kandimalla et al, 2021 ) function throughout autophagic general processes and mitochondria-specific processes and affect the balance between mitophagy, mitochondrial biogenesis, and mitochondrial dynamics. Second, concerning high AD prevalence in females, it is recommended to highlight the probable role of gender differences or interference in various behavior assessments or molecular indicators in clinical or non-clinical studies in order to find more meticulous findings underlying the complicated effects of APOE genotype.…”

Mitophagy: An Emergence of New Player in Alzheimer’s Disease

“…In this regard, there are several small molecule inhibitors are being tested and have shown promising effects in modulating the function of various proteins involved in AD development and progression. One such molecule is DRP1 whose inhibitors i.e., Diethyl(3,4-dihydroxyphenethylamino) (quinolin-4-yl) methyl phosphonate (DDQ), mitochondrial division inhibitor 1 (Mdivi-1) and Dynasore have shown efficacy in preclinical studies in AD ( Kandimalla et al, 2021 ; Medala et al, 2021 ).…”