Role of LRP1 in Alzheimer’s disease

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 (Aβ) and tau efflux. We found that deletion of LRP1 in the ChP leads to a significant decrease in Aβ 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 Aβ or tau. Furthermore, we observed that diet-induced overnutrition impairs Aβ 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 Aβ 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 Aβ and tau accumulation in the brain, leading to AD. Obesity further aggravates LRP1-dependent Aβ and tau efflux, accelerating cognitive decline. To this end, we will (i) establish the role of LRP1 in controlling Aβ 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 Aβ and tau efflux. The data generated from these timely studies may offer new insights into the underlying mechanisms of LRP1-dependent Aβ and tau clearance in the etiopathogenesis of AD and provide new therapeutic targets for AD and related dementia.