Work

Role of LRP1 in the pathogenesis of Alzheimer's disease: evidence from clinical and preclinical studies

Year: 2017

Type: review

Abstract: receptor 2 (apoER2), sortilin-related receptor (SorLA/ LR11), LRP5, and LRP6.These receptors have distinct physiological or pathophysiolgical roles, likely due to differences in their affinity to ligands, protein stability, endocytosis rate, signaling potency, cellular localization, and tissue expression pattern.While these receptors bind diverse extracellular ligands, some of them recognize key molecules in the pathogenesis of Alzheimer's disease (AD), such as apoE and amyloid- peptides (As) for cellular trafficking and/or signaling pathways.Given that the 4 allele of the APOE gene (APOE4) is the strongest genetic risk factor for AD among the three human alleles (2, 3, and 4), the potential contributions of LDLR family members to AD development have attracted great interest by many laboratories around the world for over two decades (1, 2).Cumulative evidence from preclinical studies using cellular or animal studies indicates that LDLR family members can contribute to AD pathogenesis through modulating A accumulation or neurodegenerative processes.However, as there are currently no complete cellular or animal models that can recapitulate all pathological features of AD, parallel understanding between cellular/animal studies and human studies is necessary to define the specific role of any molecule in AD pathogenesis.Herein, among the LDLR family members, we comprehensively discuss the roles of LRP1 in AD pathogenesis by reviewing both preclinical studies using cellular/animal models, and clinical studies analyzing human samples/cohorts.We will specifically review current knowledge regarding: 1) LRP1 expression during AD progression, 2) contribution of Abstract Among the LDL receptor (LDLR) family members, the roles of LDLR-related protein (LRP)1 in the pathogenesis of Alzheimer's disease (AD), especially late-onset AD, have been the most studied by genetic, neuropathological, and biomarker analyses (clinical studies) or cellular and animal model systems (preclinical studies) over the last 25 years.Although there are some conflicting reports, accumulating evidence from preclinical studies indicates that LRP1 not only regulates the metabolism of amyloid- peptides (As) in the brain and periphery, but also maintains brain homeostasis, impairment of which likely contributes to AD development in A-independent manners.Several preclinical studies have also demonstrated an involvement of LRP1 in regulating the pathogenic role of apoE, whose gene is the strongest genetic risk factor for AD.Nonetheless, evidence from clinical studies is not sufficient to conclude how LRP1 contributes to AD development.Thus, despite very promising results from preclinical studies, the role of LRP1 in AD pathogenesis remains to be further clarified.In this review, we discuss the potential mechanisms underlying how LRP1 affects AD pathogenesis through A-dependent and -independent pathways by reviewing both clinical and preclinical studies.We also discuss potential therapeutic strategies for AD by targeting LRP1.-Shinohara,M., M. Tachibana, T. Kanekiyo, and G. Bu.Role of LRP1 in the pathogenesis of Alzheimer's disease: evidence from clinical and preclinical studies.

Source: Journal of Lipid Research

DOI: 10.1194/jlr.r075796

Authors: Mitsuru Shinohara, Masaya Tachibana, Takahisa Kanekiyo, Guojun Bu

Institutions: Mayo Clinic, Mayo Clinic in Florida

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Cellular and Molecular Neuroscience

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,430