Alzheimer?s disease affects more than 5.5 million people of all ages in US and 200,000 peoples younger than 65 also develop early Alzheimer symptoms, creating tremendous burdens for patients, their families and communities. These patients show chronic/progressive memory dysfunction and dementia at late old ages. Until now all clinical trials for Alzheimer?s disease treatment have failed. Regardless of many animal models with genetic manipulations to exhibit chronic pathogenesis of this disease, it remains unknown how Alzheimer?s disease memory dysfunction/dementia symptoms(both familial and sporadic) evolve from normal brain state at early young ages to pathological memory dysfunction/neurodegeneration state at late old ages. Along this whole transitioning course, Alzheimer patients? sleep patterns have dramatically reduced slow-wave sleep(SWS) duration and relatively increased rapid eye-movement(REM) sleep, which will likely elevate cortical/hippocampal neuron excitability and play determined roles in Alzheimer?s disease pathogenesis. Compatible with this idea, preclinical silent epileptic activity in hippocampus has been recorded from sleeping Alzheimer patients[1] and sleep deprivation can dramatically increase amyloid-? peptides[2]/APOE ?4 level in brain[3, 4]. In addition, amyloid-? peptides are already present in different cortex areas before memory dysfunction and dementia manifest/are noticeable[5]. Thus, this proposal will apply one finding (sleep-like slow- wave oscillations(SWOs) induced state-dependent homeostatic synaptic potentiation) from my current R01 work to study pathophysiological mechanism at early stage of Alzheimer?s disease, using a 5XFAD mouse model and human amyloid-? peptide extracts. Specifically, we hypothesize that sleep-like cortical neuron up- state activity during sleep can cause state-dependent synaptic potentiation in hippocampal CA1 pyramidal neurons from both wide-type and 5XFAD Alzheimer?s model at young ages. Moreover, more up-state activity coming from cortical neurons during REM sleep in 5XFAD mice can chronically/progressively saturate excitatory synaptic strength of hippocampal CA1 pyramidal neurons before synaptic disruption along the ageing course. Consequentially, these saturated synaptic events can ferociously drive up generation of high level amyloid-? peptides in 5XFAD mice, which can suppress this state-dependent excitatory synaptic saturation in hippocampal CA1 pyramidal neurons and lead to synaptic attenuation and disruption. Thus, it is the chronic increased neuronal hyperexcitability/saturated excitatory synaptic activity in pyramidal neurons during altered SWS/REM sleep in 5XFAD mice that viciously drive up amyloid-? peptide generation. Eventually, these high-level amyloid-? peptides form insoluble fibrillar plaques(with tau protein neurofibrillary tangles to involve subsequently[5]), transitioning to early stage of Alzheimer?s disease with neurodegeneration at late old ages. This will offer a novel/unified mechanism on pathophysiology/pathogenesis in both familial and sporadic Alzheimer?s diseases.
Alzheimer's disease affects almost 5 million people in US. Until now recent trials of Alzheimer's disease treatment have failed and prompt new mechanisms in this field, regardless of many amyloid-? plaque hypothesis of this disease. This proposal will propose that sleep-state brain activity drives up the pathogenesis of this disease and develop a novel pathogenesis mechanism for Alzheimer's disease.
