Degeneration and energy shortage in the suprachiasmatic nucleus underlies the circadian rhythm disturbance in ApoE−/− mice: implications for Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) patients suffer sleep disorders and circadian rhythm disturbances (CRDs). The underlying mechanisms are incompletely understood, and treatments are lacking. In this study, we characterized the locomotor activity, clock gene expression, morphological degeneration and energy metabolism of suprachiasmatic nucleus (SCN), together with retinal light sensing, in ApoE−/− mice, a model for AD. Compared with the control C57BL/6J mice, ApoE−/− mice exhibited disordered circadian locomotor activity under dim light and constant darkness, with impaired re-entrainment to phase change schedules. Decreased retinal melanopsin expression, together with amyloidosis and tau deposition, was evident in ApoE−/− mice. Mitochondrial and synaptic deterioration, altered SIRT1-mediated energy metabolism and clock gene expression were also observed in ApoE−/− SCN. Supplementation with fat or ketone bodies but not glucose, or intraperitoneal administration of nicotinamide, restored the locomotor rhythmicity and circadian expression of SIRT1 and clock genes, as well as reducing neurodegeneration. Taken together, ApoE deficiency induced degeneration and a significant disturbance in the SCN rhythmicity. Decline of retinal light sensing and SCN structural and metabolic deteriorations represented the major pathologies accounting for the CRDs in ApoE−/− mice. Our curative experiments may help develop future therapies to treat the CRDs and sleep disorders in AD patients.

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