Synapsin-Promoted Caveolin-1 Overexpression Maintains Mitochondrial Morphology and Function in PSAPP Alzheimer’s Disease Mice

Abstract

Mitochondrial dysfunction plays a pivotal role in the Alzheimer’s Disease (AD) pathology. Disrupted mitochondrial dynamics (i.e., fusion/fission balance), which are essential for normal mitochondria structure and function, are documented in AD. Caveolin-1 (Cav-1), a membrane/lipid raft (MLR) scaffolding protein regulates metabolic pathways in several different cell types such as hepatocytes and cancer cells. Previously, we have shown decreased expression of Cav-1 in the hippocampus of 9-month (m) old PSAPP mice, while hippocampal overexpression of neuron-targeted Cav-1 using the synapsin promoter (i.e., SynCav1) preserved cognitive function, neuronal morphology, and synaptic ultrastructure in 9 and 12 m PSAPP mice. Considering the central role of energy production in maintaining normal neuronal and synaptic function and survival, the present study reveals that PSAPP mice exhibit disrupted mitochondrial distribution, morphometry, and respiration. In contrast, SynCav1 mitigates mitochondrial damage and loss and enhances mitochondrial respiration. Furthermore, by examining mitochondrial dynamics, we found that PSAPP mice showed a significant increase in the phosphorylation of mitochondrial dynamin-related GTPase protein (DRP1), resulting in excessive mitochondria fragmentation and dysfunction. In contrast, hippocampal delivery of SynCav1 significantly decreased p-DRP1 and augmented the level of the mitochondrial fusion protein, mitofusin1 (Mfn1) in PSAPP mice, a molecular event, which may mechanistically explain for the preserved balance of mitochondria fission/fusion and metabolic resilience in 12 m PSAPP-SynCav1 mice. Our data demonstrate the critical role for Cav-1 in maintaining normal mitochondrial morphology and function through affecting mitochondrial dynamics and explain a molecular and cellular mechanism underlying the previously reported neuroprotective and cognitive preservation induced by SynCav1 in PSAPP mouse model of AD.

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 ).…”

Age-Dependent Behavioral and Metabolic Assessment of AppNL−G−F/NL−G−F Knock-in (KI) Mice

“…In the AD brain, both clinical and preclinical evidence has shown disrupted mitochondrial dynamics, including excessive fission and decreased fusion activity. This imbalanced dynamic change will result in failure of clearance of the damaged mitochondria and impaired axonal mitochondrial transport and exacerbate mitochondrial DNA (mtDNA) changes (Hirai et al, 2001;Manczak et al, 2018;Pickett et al, 2018;Wang et al, 2021a). The present study revealed a significant decrease in hippocampal MFN2 accompanied by a wide range of mitochondrial alterations from early-stage (6-m) APPKI mice.…”

“…A separate cohort of 3-m APPKI mice were used in this experiment. Mice were euthanized, and hippocampi were collected and processed immediately on ice for mitochondrial function assessment (Kilbaugh et al, 2015;Wang et al, 2021a). An Oroboros O2k respirometer was used to assess oxygen consumption rate.…”

Catalpol Mitigates Alzheimer's Disease Progression by Promoting the Expression of Neural Stem Cell Exosomes Released miR-138-5p

“…It regulates the integrity of neurons and plays a fundamental role for synaptic and neuroplasticity. Recent researches have demonstrated that decreased Cav-1 is significantly related to AD progression and promoted Cav-1 level by transgenic manner in hippocampus effectively ameliorated the cognitive performance of AD mice (Wang et al 2021 ). In the present study, we found that the level of Cav-1 in the hippocampus of AD mice was upregulated after Ca treatment, whereas significantly downregulated upon miR-138-5p knockdown, suggesting Ca may also mediate AD progression though miR-138-5p/Cav-1 axis.…”