APP Regulates Microglial Phenotype in a Mouse Model of Alzheimer's Disease

Aug 12, 2016The Journal of neuroscience : the official journal of the Society for Neuroscience

APP Influences Immune Cell Behavior in a Mouse Model of Alzheimer's Disease

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Abstract

Oligomeric amyloid β (Aβ) reduced microglial activation in APP knock-out mice compared to wild-type mice.

Microglial cultures showed cytokine secretion in response to fibrillar Aβ, but not to oligomeric Aβ in APP knock-out cells.
Oligomeric Aβ binds to amyloid precursor protein (APP), which is necessary for its ability to stimulate microglial activity.
Intracerebroventricular infusions of oligomeric Aβ led to less microgliosis in APP knock-out mice than in wild-type mice.
Crossing APP knock-out mice with an APP/PS1 transgenic line resulted in lower microgliosis and cytokine levels, along with improved memory despite the presence of Aβ plaques.
These findings suggest a novel role for APP in promoting a proinflammatory response in microglia during Alzheimer's disease.

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UNLABELLED: Prior work suggests that amyloid precursor protein (APP) can function as a proinflammatory receptor on immune cells, such as monocytes and microglia. Therefore, we hypothesized that APP serves this function in microglia during Alzheimer's disease. Although fibrillar amyloid β (Aβ)-stimulated cytokine secretion from both wild-type and APP knock-out (mAPP(-/-)) microglial cultures, oligomeric Aβ was unable to stimulate increased secretion from mAPP(-/-) cells. This was consistent with an ability of oligomeric Aβ to bind APP. Similarly, intracerebroventricular infusions of oligomeric Aβ produced less microgliosis in mAPP(-/-) mice compared with wild-type mice. The mAPP(-/-) mice crossed to an APP/PS1 transgenic mouse line demonstrated reduced microgliosis and cytokine levels and improved memory compared with wild-type mice despite robust fibrillar Aβ plaque deposition. These data define a novel function for microglial APP in regulating their ability to acquire a proinflammatory phenotype during disease.

SIGNIFICANCE STATEMENT: A hallmark of Alzheimer's disease (AD) brains is the accumulation of amyloid β (Aβ) peptide within plaques robustly invested with reactive microglia. This supports the notion that Aβ stimulation of microglial activation is one source of brain inflammatory changes during disease. Aβ is a cleavage product of the ubiquitously expressed amyloid precursor protein (APP) and is able to self-associate into a wide variety of differently sized and structurally distinct multimers. In this study, we demonstrate both in vitro and in vivo that nonfibrillar, oligomeric forms of Aβ are able to interact with the parent APP protein to stimulate microglial activation. This provides a mechanism by which metabolism of APP results in possible autocrine or paracrine Aβ production to drive the microgliosis associated with AD brains.

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APP Regulates Microglial Phenotype in a Mouse Model of Alzheimer's Disease

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