Gain of PITRM1 peptidase in cortical neurons affords protection of mitochondrial and synaptic function in an advanced age mouse model of Alzheimer's disease.

Fang Du, Qing Yu, Shijun Yan, Zhihua Zhang, Jhansi Rani Vangavaragu, Doris Chen, Shi Fang Yan, Shirley ShiDu Yan

Aging cell 2021 May

filter terms:

Mitochondrial dysfunction is one of the early pathological features of Alzheimer's disease (AD). Accumulation of cerebral and mitochondrial Aβ links to mitochondrial and synaptic toxicity. We have previously demonstrated the mechanism by which presequence peptidase (PITRM1)-mediated clearance of mitochondrial Aβ contributes to mitochondrial and cerebral amyloid pathology and mitochondrial and synaptic stress in adult transgenic AD mice overexpressing Aβ up to 12 months old. Here, we investigate the effect of PITRM1 in an advanced age AD mouse model (up to 19-24 months) to address the fundamental unexplored question of whether restoration/gain of PITRM1 function protects against mitochondrial and synaptic dysfunction associated with Aβ accumulation and whether this protection is maintained even at later ages featuring profound amyloid pathology and synaptic failure. Using newly developed aged PITRM1/Aβ-producing AD mice, we first uncovered reduction in PITRM1 expression in AD-affected cortex of AD mice at 19-24 months of age. Increasing neuronal PITRM1 activity/expression re-established mitochondrial respiration, suppressed reactive oxygen species, improved synaptic function, and reduced loss of synapses even at advanced ages (up to 19-24 months). Notably, loss of PITRM1 proteolytic activity resulted in Aβ accumulation and failure to rescue mitochondrial and synaptic function, suggesting that PITRM1 activity is required for the degradation and clearance of mitochondrial Aβ and Aβ deposition. These data indicate that augmenting PITRM1 function results in persistent life-long protection against Aβ toxicity in an AD mouse model. Therefore, augmenting PITRM1 function may enhance Aβ clearance in mitochondria, thereby maintaining mitochondrial integrity and ultimately slowing the progression of AD. © 2021 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Citation

Fang Du, Qing Yu, Shijun Yan, Zhihua Zhang, Jhansi Rani Vangavaragu, Doris Chen, Shi Fang Yan, Shirley ShiDu Yan. Gain of PITRM1 peptidase in cortical neurons affords protection of mitochondrial and synaptic function in an advanced age mouse model of Alzheimer's disease. Aging cell. 2021 May;20(5):e13368