The Impacts of Sleep on Memory Consolidation in Alzheimer's Disease Animals

In Taiwan, there are about 4-10% people aged 65 years or older suffering from dementia. Alzheimer disease (AD) is the most common cause of dementia. Amyloid-beta (Aβ) is the main component of senile plaques, which are pathological markers of AD, and Aβhas been considered to play the most important role in the pathogenesis of AD. Neprilysin, on the other hand, degrades Aβand might be able to reverse AD. In addition to cognitive dysfunction, AD patients may present behavioral and psychological symptoms of dementia (BPSD). Sleep-wake cycle disturbance, the major outward presentation of circadian rhythm disarrangement, is a very common BPSD for AD. In transgenic AD animals, the sun-downing phenomenon, similar to the common manifestation of circadian rhythm disarrangement in AD patients, is also noted. The sleep process is important to maintaining neurocognitive functions, including memory consolidation. Different types of learning might be associated with unique sleep-related memory consolidation mechanisms that work in different brain regions and at different sleep stages, such as rapid eye movement (REM) sleep or non-REM, throughout the night. It is well documented that REM sleep, initiated by acetylcholine at brainstem is impaired in AD patients. Nitric oxide (NO) produced by NO synthases (NOS) is important for both REM maintenance and memory consolidation. In our previous study, inducible NOS (iNOS) expression increased in REM sleep among cognitive impairment patients. REM sleep and NO pathway are important for memory consolidation in AD. Sleep disturbance could be a cause for further cognitive deterioration, such as impairment of memory consolidation, in AD patients. The accumulation of Aβ in AD brain, especially in the brainstem, could interfere with the REM sleep initiation and maintenance. In this study, we will explore the behavioral and molecular changes in AD animal to clarify the role of REM sleep in memory consolidation among AD animals and the possible molecular mechanisms for these disarrangements. In summary, the proposal will include AD animals and controls.All of them will undergo polysomnography (PSG)-like examination under regular light-dark cycle and will take water maze tests for evaluation of memory consolidation with or without REM deprivation. In the mean time, we will explore the role of Aβaccumulation in REM sleep and memory consolidation by pathological correlation, survey about changes of profiled gene expression, including iNOS, eNOS, BDNF, PER1, melatonin, Aβ, tau and all the changes after Aβburden reduction by neprilysin enhancers.