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Published on: January 30, 2014
APP Regulates Microglial Phenotype in a Mouse Model of Alzheimer's Disease
Gunjan D Manocha1, Angela M Floden1, Keiko Rausch1
1Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58203.
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.
Insights
Amyloid precursor protein (APP) on microglia drives Alzheimer's disease inflammation. Removing APP reduces microglial activation and improves memory in mouse models, revealing a novel therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) plaques and neuroinflammation, with microglia playing a key role.
- Amyloid precursor protein (APP) is implicated in AD pathogenesis and may act as a receptor on immune cells like microglia.
- Microglial activation by Aβ contributes to the inflammatory changes observed in AD brains.
Purpose of the Study:
- To investigate the role of microglial amyloid precursor protein (APP) in mediating neuroinflammation during Alzheimer's disease.
- To determine if APP functions as a receptor for oligomeric amyloid-beta (Aβ) in stimulating microglial pro-inflammatory responses.
Main Methods:
- Utilized microglial cell cultures from wild-type and APP knock-out (mAPP(-/-)) mice to assess cytokine secretion in response to fibrillar and oligomeric Aβ.
- Administered intracerebroventricular infusions of oligomeric Aβ into mAPP(-/-) and wild-type mice to evaluate microgliosis in vivo.
- Generated mAPP(-/-) mice crossed with APP/PS1 transgenic mice to assess the impact of microglial APP deletion on AD pathology and cognitive function.
Main Results:
- Oligomeric Aβ, but not fibrillar Aβ, stimulated cytokine secretion from wild-type microglia but not mAPP(-/-) microglia, indicating APP's role in sensing oligomeric Aβ.
- Intracerebroventricular infusion of oligomeric Aβ led to reduced microgliosis in mAPP(-/-) mice compared to wild-type controls.
- APP/PS1 mice lacking microglial APP exhibited reduced microgliosis, lower cytokine levels, and improved memory, despite substantial Aβ plaque deposition.
Conclusions:
- Microglial APP acts as a receptor for oligomeric Aβ, mediating the pro-inflammatory activation of microglia in Alzheimer's disease.
- Deletion of microglial APP ameliorates neuroinflammation and cognitive deficits in AD mouse models, highlighting APP's critical role in AD pathogenesis.
- Targeting microglial APP represents a potential therapeutic strategy for mitigating neuroinflammation and cognitive decline in Alzheimer's disease.
