Chronic Sleep Restriction Induces Cognitive Deficits and Cortical Beta-Amyloid Deposition in Mice via BACE1-Antisense Activation

AimsTo clarify the correlation between chronic sleep restriction (CSR) and sporadic Alzheimer disease (AD), we determined in wild-type mice the impact of CSR, on cognitive performance, beta-amyloid (A) peptides, and its feed-forward regulators regarding AD pathogenesis.MethodsSixteen nine-month-old C57BL/6 male mice were equally divided into the CSR and control groups. CSR was achieved by application of a slowly rotating drum for 2months. The Morris water maze test was used to assess cognitive impairment. The concentrations of A peptides, amyloid precursor protein (APP) and -secretase 1 (BACE1), and the mRNA levels of BACE1 and BACE1-antisense (BACE1-AS) were measured.ResultsFollowing CSR, impairments of spatial learning and memory consolidation were observed in the mice, accompanied by A plaque deposition and an increased A concentration in the prefrontal and temporal lobe cortex. CSR also upregulated the -secretase-induced cleavage of APP by increasing the protein and mRNA levels of BACE1, particularly the BACE1-AS.ConclusionsThis study shows that a CSR accelerates AD pathogenesis in wild-type mice. An upregulation of the BACE1 pathway appears to participate in both cortical A plaque deposition and memory impairment caused by CSR. BACE1-AS is likely activated to initiate a cascade of events that lead to AD pathogenesis. Our study provides, therefore, a molecular mechanism that links CSR to sporadic AD.