Alzheimer’s disease (AD) is a serious public health problem. AD is the most common cause of dementia, which
is pathologically characterized by the accumulation of amyloid plaques and tau-containing neurofibrillary tangles
in the brain. AD is clinically manifested as progressive memory loss and cognitive impairment, leading to
prolonged disability and eventual death. Yet, the cellular mechanisms underlying AD pathogenesis are not fully
understood and no effective therapy is currently available for AD. Our preliminary data point to the important role
of low-density lipoprotein receptor-related protein 1 (LRP1) in the choroid plexus (ChP) and tanycytes that is
significant in the optimal regulation of amyloid-beta (A¿) and tau efflux. We found that deletion of LRP1 in the
ChP leads to a significant decrease in A¿ clearance from the CSF into circulation. Interestingly, we also found
that LRP1 in tanycytes is necessary to regulate tau clearance from the CSF to the blood. Importantly, LRP1
physically binds to leptin receptor (LepR) in response to A¿ or tau. Furthermore, we observed that diet-induced
overnutrition impairs A¿ clearance from the brain and obesity-related metabolic parameters negatively correlate
with short-term memory. We therefore hypothesize that LRP1 in the ChP and tanycytes is essential for regulating
A¿ and tau clearance, which is coupled with the LepR to exert transcytosis of these proteins from the CSF to
circulation. Thus, an impaired LRP1 action causes A¿ and tau accumulation in the brain, leading to AD. Obesity
further aggravates LRP1-dependent A¿ and tau efflux, accelerating cognitive decline. To this end, we will (i)
establish the role of LRP1 in controlling A¿ efflux in the choroid plexus; (ii) explore the significance of LRP1 in
regulating tau transport in tanycytes. To accomplish these goals, we will employ state-of-the-art biochemical,
molecular, cellular, and metabolic physiological techniques, including genetically engineered tissue-specific
transgenic mouse models, in vivo live two-photon imaging, and Cre-inducible AAV system. These studies will
provide a unique opportunity to establish a novel mechanism implicating LRP1 as a key determinant of A¿ and
tau efflux. The data generated from these timely studies may offer new insights into the underlying mechanisms
of LRP1-dependent A¿ and tau clearance in the etiopathogenesis of AD and provide new therapeutic targets for
AD and related dementia.