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

Mitochondrial dysfunction is one of the early pathological features of Alzheimer's disease (AD). Accumulation of cerebral and mitochondrial A beta links to mitochondrial and synaptic toxicity. We have previously demonstrated the mechanism by which presequence peptidase (PITRM1)-mediated clearance of mitochondrial A beta contributes to mitochondrial and cerebral amyloid pathology and mitochondrial and synaptic stress in adult transgenic AD mice overexpressing A beta 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 A beta accumulation and whether this protection is maintained even at later ages featuring profound amyloid pathology and synaptic failure. Using newly developed aged PITRM1/A beta-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 A beta accumulation and failure to rescue mitochondrial and synaptic function, suggesting that PITRM1 activity is required for the degradation and clearance of mitochondrial A beta and A beta deposition. These data indicate that augmenting PITRM1 function results in persistent life-long protection against A beta toxicity in an AD mouse model. Therefore, augmenting PITRM1 function may enhance A beta clearance in mitochondria, thereby maintaining mitochondrial integrity and ultimately slowing the progression of AD.