O2‐12‐05: Isoform‐specific rcan1 overexpression promotes age‐dependent mitochondrial dysregulation related to neurodegeneration in Alzheimer's disease

Patients with Down syndrome (DS) develop early onset AD, suggesting that overexpressed chromosome 21 genes like Regulator of Calcineurin 1 (RCAN1) play a role in AD pathogenesis. RCAN1 levels are elevated in DS and AD and increase normally with aging in the human brain. However, RCAN1 generates several protein isoforms whose contributions to the aging-related progression of AD remain elusive. Using Western analyses, we found that the RCAN1.1S isoform is increased in the brains of sporadic AD patients. To determine if this increase is symptomatic or causal in AD, we generated a new mouse model with brain-restricted human RCAN1.1S overexpression. Using a battery of converging approaches: mouse behavior, electrophysiology, biochemistry, and histology, we measured the effects of aging and RCAN1.1S overexpression on several markers of AD neuropathophysiology. We show that chronically increased RCAN1.1S expression causes age-dependent memory and synaptic plasticity deficits. We show that RCAN1.1S overexpression causes the development of tau hyperphosphorylation, oxidative stress, and mitochondrial defects in the adult mouse hippocampus. We identify a novel pathogenic mechanism mediated by chronic excessive RCAN1.1S signaling during aging: dynamin-related protein 1 (DRP1) dysregulation of mitochondrial fission. Based on these findings, we propose that chronic RCAN1.1S overexpression during aging alters DRP1-mediated mitochondrial fission as a causal factor in AD-related progressive neurodegeneration.