Dataset Information

Pericyte loss influences Alzheimer-like neurodegeneration in mice.

ABSTRACT: Pericytes are cells in the blood-brain barrier that degenerate in Alzheimer's disease (AD), a neurological disorder associated with neurovascular dysfunction, abnormal elevation of amyloid ?-peptide (A?), tau pathology and neuronal loss. Whether pericyte degeneration can influence AD-like neurodegeneration and contribute to disease pathogenesis remains, however, unknown. Here we show that in mice overexpressing A?-precursor protein, pericyte loss elevates brain A?40 and A?42 levels and accelerates amyloid angiopathy and cerebral ?-amyloidosis by diminishing clearance of soluble A?40 and A?42 from brain interstitial fluid prior to A? deposition. We further show that pericyte deficiency leads to the development of tau pathology and an early neuronal loss that is normally absent in A?-precursor protein transgenic mice, resulting in cognitive decline. Our data suggest that pericytes control multiple steps of AD-like neurodegeneration pathogenic cascade in A?-precursor protein-overexpressing mice. Therefore, pericytes may represent a novel therapeutic target to modify disease progression in AD.

SUBMITTER: Sagare AP

PROVIDER: S-EPMC3945879 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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Pericyte loss influences Alzheimer-like neurodegeneration in mice.

Sagare Abhay P AP Bell Robert D RD Zhao Zhen Z Ma Qingyi Q Winkler Ethan A EA Ramanathan Anita A Zlokovic Berislav V BV

Nature communications 20130101

Pericytes are cells in the blood-brain barrier that degenerate in Alzheimer's disease (AD), a neurological disorder associated with neurovascular dysfunction, abnormal elevation of amyloid β-peptide (Aβ), tau pathology and neuronal loss. Whether pericyte degeneration can influence AD-like neurodegeneration and contribute to disease pathogenesis remains, however, unknown. Here we show that in mice overexpressing Aβ-precursor protein, pericyte loss elevates brain Aβ40 and Aβ42 levels and accelerat ...[more]

PMID: 24336108

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Project description:BackgroundObesity is associated with multiple diseases, but it is unclear how obesity promotes progressive tissue damage. Recovery from injury requires repair, an energy-expensive process that is coupled to energy availability at the cellular level. The satiety factor, leptin, is a key component of the sensor that matches cellular energy utilization to available energy supplies. Leptin deficiency signals energy depletion, whereas activating the Hedgehog pathway drives energy-consuming activities. Tissue repair is impaired in mice that are obese due to genetic leptin deficiency. Tissue repair is also blocked and obesity enhanced by inhibiting Hedgehog activity. We evaluated the hypothesis that loss of leptin silences Hedgehog signaling in pericytes, multipotent leptin-target cells that regulate a variety of responses that are often defective in obesity, including tissue repair and adipocyte differentiation.ResultsWe found that pericytes from liver and white adipose tissue require leptin to maintain expression of the Hedgehog co-receptor, Smoothened, which controls the activities of Hedgehog-regulated Gli transcription factors that orchestrate gene expression programs that dictate pericyte fate. Smoothened suppression prevents liver pericytes from being reprogrammed into myofibroblasts, but stimulates adipose-derived pericytes to become white adipocytes. Progressive Hedgehog pathway decay promotes senescence in leptin-deficient liver pericytes, which, in turn, generate paracrine signals that cause neighboring hepatocytes to become fatty and less proliferative, enhancing vulnerability to liver damage.ConclusionsLeptin-responsive pericytes evaluate energy availability to inform tissue construction by modulating Hedgehog pathway activity and thus, are at the root of progressive obesity-related tissue pathology. Leptin deficiency inhibits Hedgehog signaling in pericytes to trigger a pericytopathy that promotes both adiposity and obesity-related tissue damage.

Dataset Information

Pericyte loss influences Alzheimer-like neurodegeneration in mice.

Publications

Pericyte loss influences Alzheimer-like neurodegeneration in mice.

Similar Datasets

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