Presequence protease reverses mitochondria‐specific amyloid‐β‐induced mitophagy to protect mitochondria

Abstract

Amyloid‐β (Aβ) peptide is accumulated in the mitochondria and has been shown to play a central role in the development of Alzheimer's disease (AD). It has been shown that exposure of neurons to aggregated Aβ can result in damaged mitochondria and dysregulated mitophagy, indicating that changes in the Aβ content of mitochondria may affect the levels of mitophagy and interfere with the progression of AD. However, the direct influence of mitochondrial Aβ on mitophagy has not been elucidated. In the present study, the effect of the mitochondria‐specific Aβ was assessed following a direct change of Aβ content in the mitochondria. We directly change mitochondrial Aβ by transfecting cells with mitochondria‐associated plasmids, including the mitochondrial outer membrane protein translocase 22 (TOMM22) and 40 (TOMM40) or presequence protease (PreP) overexpression plasmids. The changes in the levels of mitophagy were assessed by TEM, Western blot, mito‐Keima construct, organelle tracker, and probe JC‐1 assay. We demonstrated that increased mitochondrial Aβ content enhance mitophagy levels; overexpression of PreP could reverse the mitochondrial Aβ‐induced mitophagy levels in vivo and in vitro by reversing the levels of reactive oxygen species (ROS) and the mitochondrial membrane potential. The data provide novel insight into the role of mitochondria‐specific Aβ in the progression of AD pathophysiology.

Mitochondria in Alzheimer’s Disease Pathogenesis

“…Dou and Tan transfected SHSY-5Y human neuroblastoma cells with plasmids harboring mitochondrial outer membrane protein translocase (TOMM)22 and TOMM40 to directly augment mitochondrial Aβ content. They found that increased Aβ content in the mitochondria enhanced mitophagy, and this could be reversed by transfection with a plasmid harboring presequence protease, responsible for Aβ degradation [76]. In a separate study, presequence protease activity was found by Alikhani and colleagues to be significantly lower in mitochondria isolated from brain tissue specimens obtained post-mortem from the temporal region of AD-affected subjects compared to age-matched controls [77].…”

Sensorineural hearing loss and cognitive impairment: three hypotheses

“…Amyloid plaques formed by β-amyloid (Aβ) and neurofibrillary tangles formed by abnormally modified tau proteins are the hallmarks of AD ( Skouras et al, 2020 ; Ossenkoppele et al, 2022 ; Tautou et al, 2023 ). Aβ is a peptide produced by hydrolysis of amyloid precursor protein (APP), and excess Aβ accumulation in mitochondria activates astrocytes and microglia, damages neurons ( Huang et al, 2023 ), and induces mitochondrial autophagy, promoting reactive oxygen species (ROS) production and accelerating neural oxidation ( Dou and Tan, 2023 ). At the same time, over-phosphorylation of tau protein eliminates its ability to form and maintain stable microtubules, reduces the dissociation of microtubule protein molecules, and induces microtubule bundling ( Kandimalla et al, 2018 ; Solas et al, 2023 ; Zhang et al, 2023 ).…”

Current Advances in Mitochondrial Targeted Interventions in Alzheimer’s Disease

“…However, whilst the interaction of Aβ with HSD10 causes a prompt increase in ROS levels, namely O 2 · − and H 2 O 2 , and a loss of mitochondria function [ 50 ], PreP activity was found to be decreased in AD brains and AD transgenic mouse brains, which also presented higher levels of oxidative products in their mitochondria [ 49 ]. It has been therefore proposed that modulating PreP activity could be a feasible strategy to control the mitochondrial Aβ content and mitochondrial oxidative stress [ 51 , 52 ]. Moreover, a recent in vitro study performed in iPSC-derived neurons and SY5Y cells transfected with an AβPP construct identified an undescribed correlation between the mitochondrial membrane potential, AβPP mitochondrial localization, and Aβ secretion [ 53 ].…”