This application corresponds to Notice of Special Interest: Alzheimer’s-focused administrative supplements for NIH grants that are not focused on Alzheimer’s diseases. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by memory loss, impaired cognition and eventual functional disability and death. AD affects an estimated 5.8 million people in the United States with half a million new cases annually, and this number is anticipated to more than double within 30 years. Given the significant increase in the prevalence of AD in the adult populations, identification of novel targets for treating and preventing AD and its related dementias is urgently needed. The hallmark of AD pathogenesis is the accumulation of amyloid- peptide (A) plaques between nerve cells in the brain. The A accumulation is the result of an imbalance of A generation in amyloid precursor protein and its subsequent clearance. Impaired A clearance is predominantly responsible for its accumulation in sporadic or the late-onset AD rather than A overproduction. The low-density lipoprotein receptor-related protein-1 or -2 (LRP1 or LRP2) plays a role in eliminating A in the brain by promoting A uptake and degradation in astrocytes, neurons and cerebrovascular smooth muscle cells, and A transcytosis across the blood brain barrier. However, a major gap in understanding the central mechanisms underlying LRP1/2-mediated A clearance has been a lack of knowledge regarding how LRP1/2 regulates A elimination in the hypothalamic tanycytes. This could be due to a lack of an appropriate animal model that can study LRP1/2 function in the tanyctes in the context of A clearance in vivo. During the research period of the parent grant (R01DK12302, Control of leptin transport system by LRP), we have generated the mice lacking LRP2 in the tanycytes by breeding LRP2loxP/loxP with Rax-CreERT2 Knock-in mice (Rax-CreERT2; LRP2loxP/loxP). We are also currently creating the mice lacking LRP1 in the tanycytes by breeding LRP1loxP/loxP with Rax-CreERT2 mice (Rax- CreERT2; LRP1loxP/loxP). Using these models, we will test the novel hypothesis that LRP1/2 in the tanycytes of the hypothalamus is necessary to clear A from the brain to the bloodstream and dysfunction of LRP1/2 in the tanycytes leads to A accumulation in the brain, leading to AD. The data generated from these studies may offer further insights into the pathogenesis of AD-related disorders and lead to new therapeutic targets for the treatment of AD.