Mitochondrial Deficits With Neural and Social Damage in Early-Stage Alzheimer's Disease Model Mice.

Afzal Misrani,Adeel Ahmed,Jiajia Zhang,Jinxiang Jiang,Sumaiya Tabassum,Cheng Long,Xiangmao Chen,Sidra Tabassum,Jianwen Zhou,Xiaoyi Feng,Qingwei Huo,Sha Liu,Li Yang

doi:10.3389/fnagi.2021.748388

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide. Mitochondrial dysfunction is thought to be an early event in the onset and progression of AD; however, the precise underlying mechanisms remain unclear. In this study, we investigated mitochondrial proteins involved in organelle dynamics, morphology and energy production in the medial prefrontal cortex (mPFC) and hippocampus (HIPP) of young (1∼2 months), adult (4∼5 months) and aged (9∼10, 12∼18 months) APP/PS1 mice. We observed increased levels of mitochondrial fission protein, Drp1, and decreased levels of ATP synthase subunit, ATP5A, leading to abnormal mitochondrial morphology, increased oxidative stress, glial activation, apoptosis, and altered neuronal morphology as early as 4∼5 months of age in APP/PS1 mice. Electrophysiological recordings revealed abnormal miniature excitatory postsynaptic current in the mPFC together with a minor connectivity change between the mPFC and HIPP, correlating with social deficits. These results suggest that abnormal mitochondrial dynamics, which worsen with disease progression, could be a biomarker of early-stage AD. Therapeutic interventions that improve mitochondrial function thus represent a promising approach for slowing the progression or delaying the onset of AD.

Highlights

Alzheimer’s disease (AD) is a progressive, multifactorial, age-dependent, neurodegenerative disorder characterized by loss of memory, impairment of cognitive and non-cognitive functions, and changes in personality and behavior (Saez-Atienzar and Masliah, 2020)
Considering the crucial role of mitochondrial fission and fusion in neuronal function, and the occurrence of mitochondrial dysfunction in AD, we first sought to determine the earliest age at which any alteration in these fission/fusion proteins occurs in amyloid precursor protein/presenilin 1 (APP/PS1) mice
Our western blotting results of medial prefrontal cortex (mPFC) extracts revealed no significant difference in the levels of Drp1 (WT: 1 ± 0.31; amyloid precursor protein (APP)/PS1: 0.87 ± 0.29; p = 0.792); Mfn1 (WT: 1 ± 0.32; APP/PS1: 0.56 ± 0.20; p = 0.321); Mfn2 (WT: 1 ± 0.35; APP/PS1: 0.89 ± 0.21; p = 0.815); optic atrophy type 1 (OPA1) (WT: 1 ± 0.43; APP/PS1: 1.04 ± 0.32; p = 0.935); and ATP5A (WT: 1 ± 0.15; APP/PS1: 1.19 ± 0.30; p = 0.607; Supplementary Figures 1A, B)

Summary

Introduction

Alzheimer’s disease (AD) is a progressive, multifactorial, age-dependent, neurodegenerative disorder characterized by loss of memory, impairment of cognitive and non-cognitive functions, and changes in personality and behavior (Saez-Atienzar and Masliah, 2020). At the cellular and molecular levels, AD is associated with loss of neurons, neurofibrillary tangles, and amyloid β (Aβ) deposits in the cortex and hippocampus (Van Der Kant et al, 2020). The mitochondrion, known as the powerhouse of the cell, is the organelle that produces the energy (in the form of adenosine triphosphate, ATP) necessary for the survival and optimal function of neurons (Spinelli and Haigis, 2018). Neurons are especially vulnerable to mitochondrial dysfunction due to their high energy demand and dependence on the respiration for ATP generation. Despite evidence suggesting that mitochondrial dysfunction (Hauptmann et al, 2009; Wang et al, 2020) and abnormal synaptic transmission (Selkoe, 2002; Styr and Slutsky, 2018) are early events, earlier than the appearance of Aβ plaques in AD pathology, which comes first has not been evaluated side-by-side

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Conclusion