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Patients with Alzheimer’s disease (AD) often have fragmentation of sleep/wake cycles and disrupted 24-h (circadian) activity. Despite this, little work has investigated the potential underlying day/night disruptions in cognition and neuronal physiology in the hippocampus. The molecular clock, an intrinsic transcription-translation feedback loop that regulates circadian behavior, may also regulate hippocampal neurophysiological activity. We hypothesized that disrupted diurnal variation in clock gene expression in the hippocampus corresponds with loss of normal day/night differences in membrane excitability, synaptic physiology, and cognition. We previously reported that the Tg-SwDI mouse model of AD has disrupted circadian locomotor rhythms and neurophysiological output of the suprachiasmatic nucleus (the primary circadian clock). Here, we report that Tg-SwDI mice failed to show day-night differences in a spatial working memory task, unlike wild-type controls that exhibited enhanced spatial working memory at night. Moreover, Tg-SwDI mice had lower levels of Per2, one of the core components of the molecular clock, at both mRNA and protein levels when compared to age-matched controls. Interestingly, we discovered neurophysiological impairments in area CA1 of the Tg-SwDI hippocampus. In controls, spontaneous inhibitory post-synaptic currents (sIPSCs) in pyramidal cells showed greater amplitude and lower inter-event interval during the day than the night. However, the normal day/night differences in sIPSCs were absent (amplitude) or reversed (inter-event interval) in pyramidal cells from Tg-SwDI mice. In control mice, current injection into CA1 pyramidal cells produced more firing during the night than during the day, but no day/night difference in excitability was observed in Tg-SwDI mice. The normal day/night difference in excitability in controls was blocked by GABA receptor inhibition. Together, these results demonstrate that the normal diurnal regulation of inhibitory transmission in the hippocampus is diminished in a mouse model of AD, leading to decreased daytime inhibition onto hippocampal CA1 pyramidal cells. Uncovering disrupted day/night differences in circadian gene regulation, hippocampal physiology, and memory in AD mouse models may provide insight into possible chronotherapeutic strategies to ameliorate Alzheimer’s disease symptoms or delay pathological onset.

Amyloid-beta (Abeta) has remained a central feature in research into Alzheimer's disease (AD). Yet the function of the amyloid-beta protein precursor (AbetaPP) and its processing products in the central nervous system is controversial. This review examines experimental literature from cell cultures to transgenic AD and brain injury models with a special emphasis on the functional role of AbetaPP and AbetaPP-derived peptides. AbetaPP knock-out mice exhibit severe metabolic abnormalities and behavioral deficits, indicating an important physiological function of AbetaPP. Also, an increasing body of evidence suggests that while Abeta is undoubtedly linked to neurodegeneration, the soluble amino-terminal fragment of AbetaPP (sAbetaPPalpha) has neuroprotective, neurotrophic, and cell adhesive functions. Moderate overexpression of human AbetaPP in rodents does not produce apparent Abeta pathology and has no significant effect on cognitive or sensorimotor behavior and, surprisingly, may even provide histological neuroprotection against focal cerebral ischemia. In contrast, phenotypes with more severe Abeta pathology show impaired cognitive performance, increased vulnerability to brain ischemia and trauma, and less favorable functional outcome even before Abeta deposition. A delicate balance in AbetaPP processing seems to determine its functional consequences. Thus, it is tempting to speculate that promotion of alpha-secretase-mediated cleavage of AbetaPP, which leads to increased sAbetaPPalpha production, provides a novel therapeutic strategy in the treatment of AD and brain injury.