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Multifunctional Nanostructure RAP-RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit.

ABSTRACT: Cerebrovascular dysfunction characterized by the neurovascular unit (NVU) impairment contributes to the pathogenesis of Alzheimer's disease (AD). In this study, a cerebrovascular-targeting multifunctional lipoprotein-biomimetic nanostructure (RAP-RL) constituted with an antagonist peptide (RAP) of receptor for advanced glycation end-products (RAGE), monosialotetrahexosyl ganglioside, and apolipoprotein E3 is developed to recover the functional NVU and normalize the cerebral vasculature. RAP-RL accumulates along the cerebral microvasculature through the specific binding of RAP to RAGE, which is overexpressed on cerebral endothelial cells in AD. It effectively accelerates the clearance of perivascular A?, normalizes the morphology and functions of cerebrovasculature, and restores the structural integrity and functions of NVU. RAP-RL markedly rescues the spatial learning and memory in APP/PS1 mice. Collectively, this study demonstrates the potential of the multifunctional nanostructure RAP-RL as a disease-modifying modality for AD treatment and provides the proof of concept that remodeling the functional NVU may represent a promising therapeutic approach toward effective intervention of AD.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC7816710 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Multifunctional Nanostructure RAP-RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit.

Zhang Qian Q Song Qingxiang Q Gu Xiao X Zheng Mengna M Wang Antian A Jiang Gan G Huang Meng M Chen Huan H Qiu Yu Y Bo Bin B Tong Shanbao S Shao Rong R Li Binyin B Wang Gang G Wang Hao H Hu Yongbo Y Chen Hongzhuan H Gao Xiaoling X

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20201210 2

Cerebrovascular dysfunction characterized by the neurovascular unit (NVU) impairment contributes to the pathogenesis of Alzheimer's disease (AD). In this study, a cerebrovascular-targeting multifunctional lipoprotein-biomimetic nanostructure (RAP-RL) constituted with an antagonist peptide (RAP) of receptor for advanced glycation end-products (RAGE), monosialotetrahexosyl ganglioside, and apolipoprotein E3 is developed to recover the functional NVU and normalize the cerebral vasculature. RAP-RL a ...[more]

PMID: 33511002

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Project description:BackgroundRecently, we and other researchers reported that brain metabolic disorders are implicated in Alzheimer's disease (AD), a progressive, devastating and incurable neurodegenerative disease. Hence, novel therapeutic approaches are urgently needed to explore potential and novel therapeutic targets/agents for the treatment of AD. The neuronal adiponectin receptor 1 (AdipoR1) is an emerging potential target for intervention in metabolic-associated AD. We aimed to validate this hypothesis and explore in-depth the therapeutic effects of an osmotin-derived adiponectin-mimetic novel nonapeptide (Os-pep) on metabolic-associated AD.MethodsWe used an Os-pep dosage regimen (5 μg/g, i.p., on alternating days for 45 days) for APP/PS1 in amyloid β oligomer-injected, transgenic adiponectin knockout (Adipo-/-) and AdipoR1 knockdown mice. After behavioral studies, brain tissues were subjected to biochemical and immunohistochemical analyses. In separate cohorts of mice, electrophysiolocal and Golgi staining experiments were performed. To validate the in vivo studies, we used human APP Swedish (swe)/Indiana (ind)-overexpressing neuroblastoma SH-SY5Y cells, which were subjected to knockdown of AdipoR1 and APMK with siRNAs, treated with Os-pep and other conditions as per the mechanistic approach, and we proceeded to perform further biochemical analyses.ResultsOur in vitro and in vivo results show that Os-pep has good safety and neuroprotection profiles and crosses the blood-brain barrier. We found reduced levels of neuronal AdipoR1 in human AD brain tissue. Os-pep stimulates AdipoR1 and its downstream target, AMP-activated protein kinase (AMPK) signaling, in AD and Adipo-/- mice. Mechanistically, in all of the in vivo and in vitro studies, Os-pep rescued aberrant neuronal metabolism by reducing neuronal insulin resistance and activated downstream insulin signaling through regulation of AdipoR1/AMPK signaling to consequently improve the memory functions of the AD and Adipo-/- mice, which was associated with improved synaptic function and long-term potentiation via an AdipoR1-dependent mechanism.ConclusionOur findings show that Os-pep activates AdipoR1/AMPK signaling and regulates neuronal insulin resistance and insulin signaling, which subsequently rescues memory deficits in AD and adiponectin-deficient models. Taken together, the results indicate that Os-pep, as an adiponectin-mimetic novel nonapeptide, is a valuable and promising potential therapeutic candidate to treat aberrant brain metabolism associated with AD and other neurodegenerative diseases.

Dataset Information

Multifunctional Nanostructure RAP-RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit.

Publications

Multifunctional Nanostructure RAP-RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit.

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