Background: Genetic, epidemiologic, and biochemical evidence suggests that apolipoprotein E, lowdensity lipoprotein receptors, and lipid metabolism play important roles in sporadic Alzheimer disease (AD). Objective: To identify novel candidate genes associated with sporadic AD. Design: We performed an unbiased microarray screen for genes differentially expressed in lymphoblasts of patients with sporadic AD and prioritized 1 gene product for further characterization in AD brain.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and neuropathological changes, including the deposition of amyloid ␤ (A␤) in senile plaques. The mechanisms causing the disease and A␤ accumulation are not well understood, but important genetic associations with apolipoprotein E genotype and involvement of lipoprotein receptors have become apparent. LR11 (also known as SorLA), a member of the low-density lipoprotein receptor family, has been identified previously as an altered transcript in microarray analyses of samples from human AD cases. Here, we show neuronal expression of the lipoprotein receptor LR11 in control brain in regions vulnerable to AD neuropathology and marked reduction of LR11 expression in these regions in AD brains before cell death. Overexpression of LR11 drastically reduces levels of extracellular A␤ and also lowers levels of total cellular amyloid precursor protein (APP). LR11 colocalizes with APP and regulates its trafficking in endocytic compartments, which are important intracellular sites for APP processing and A␤ generation. Endogenous LR11 localizes to neuronal multivesicular bodies in both rat and human brain. The robust correlation between reduced LR11 expression and AD neuropathology and its potent effects on extracellular A␤ levels suggest that this neuronal lipoprotein receptor could play an important role in AD pathogenesis.

Defining the cellular pathway(s) by which LR11 modulates amyloid-β peptide production is critical to understanding how changes in LR11 expression affect the progression of Alzheimer's disease. These results suggest that endocytic traffic of LR11, facilitated by GGA1, enhances LR11 modulation of amyloid precursor protein processing in a nonamyloidogenic manner.

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