Research ArticleAlzheimer’s Disease

Disruption of the Sleep-Wake Cycle and Diurnal Fluctuation of β-Amyloid in Mice with Alzheimer’s Disease Pathology

Science Translational Medicine  05 Sep 2012:
Vol. 4, Issue 150, pp. 150ra122
DOI: 10.1126/scitranslmed.3004291

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Don’t Let Amyloid Keep You Awake at Night

The accumulation in the brain of the neurotoxic β-amyloid (Aβ) peptide is a key event in the pathogenesis of Alzheimer’s disease (AD). Aβ accumulation in amyloid plaques begins about 10 to 15 years before cognitive decline and is already very substantial by the time memory and thinking problems begin. It is critical to determine whether there are functional and biochemical changes in the brain that are present when Aβ is accumulating but before the appearance of dementia to initiate therapy earlier as well as to assess the therapeutic effects of new drugs. Previous work has shown that soluble forms of Aβ fluctuate in the brain with the sleep-wake cycle. Now, Roh and colleagues show that diurnal fluctuation of Aβ occurs in different brain regions in young adult mice that develop accumulation of Aβ. However, Aβ fluctuation disappeared with the onset of amyloid plaque deposition, most likely due to insoluble Aβ plaques sequestering soluble forms of Aβ. Similar findings were seen in the cerebrospinal fluid of humans with genetic mutations that cause early-onset, autosomal dominant AD. Coincident with increasing Aβ accumulation, the researchers found that the amount of time mice were awake when they were supposed to be asleep increased by 50%. Actively immunizing mice with Aβ prevented amyloid plaque formation, as well as maintaining normal circadian Aβ fluctuation and normal sleep patterns. These findings suggest that changes in the sleep-wake cycle may be caused by Aβ accumulation. If analogous abnormalities in the sleep-wake cycle are present in cognitively normal and very mildly impaired humans who are developing AD pathology, the sleep-wake cycle may be a useful indicator of early brain dysfunction that could be assessed as an outcome measure in response to therapeutic interventions.