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Gain of PITRM1 peptidase in cortical neurons affords protection of mitochondrial and synaptic function in an advanced age mouse model of Alzheimer’s disease
- Source :
- Aging Cell
- Publication Year :
- 2021
- Publisher :
- Wiley, 2021.
-
Abstract
- 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.<br />Restoration/gain of neuronal PITRM1 function by enhancing its proteolytic activity in the aged AD mouse model significantly promotes synaptic mitochondrial and cerebral Aβ degradation and clearance, and thereby improves mitochondrial and synaptic functions, and alleviates loss of synapses.
- Subjects :
- Male
0301 basic medicine
Aging
Transgene
mitochondrial Aβ clearance
Mice, Transgenic
Disease
Biology
Mitochondrion
Amyloid beta-Protein Precursor
03 medical and health sciences
Cognition
0302 clinical medicine
mitochondrial proteolysis
mitochondria‐related proinflammation
Alzheimer Disease
Animals
Inflammation
Neurons
chemistry.chemical_classification
Original Paper
Reactive oxygen species
Amyloid beta-Peptides
Brain
Metalloendopeptidases
Cell Biology
Mitochondria
Cell biology
Cortex (botany)
Disease Models, Animal
Synaptic function
synaptic rescue
030104 developmental biology
chemistry
Synapses
Toxicity
Female
amyloid pathology
030217 neurology & neurosurgery
Function (biology)
Subjects
Details
- ISSN :
- 14749726 and 14749718
- Volume :
- 20
- Database :
- OpenAIRE
- Journal :
- Aging Cell
- Accession number :
- edsair.doi.dedup.....924ec90f087766f6249ec3b77224d62c