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

To 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 (Aβ) peptides, and its feed-forward regulators regarding AD pathogenesis.

This study shows that a CSR accelerates AD pathogenesis in wild-type mice. An upregulation of the BACE1 pathway appears to participate in both cortical Aβ 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.

Sixteen 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 2 months. The Morris water maze test was used to assess cognitive impairment. The concentrations of Aβ peptides, amyloid precursor protein (APP) and β-secretase 1 (BACE1), and the mRNA levels of BACE1 and BACE1-antisense (BACE1-AS) were measured.

Following CSR, impairments of spatial learning and memory consolidation were observed in the mice, accompanied by Aβ plaque deposition and an increased Aβ concentration in the prefrontal and temporal lobe cortex. CSR also upregulated the β-secretase-induced cleavage of APP by increasing the protein and mRNA levels of BACE1, particularly the BACE1-AS. Conclusions: This study shows that a CSR accelerates AD pathogenesis in wild-type mice. An upregulation of the BACE1 pathway appears to participate in both cortical Aβ 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.