期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 12, 页码 6844-6854出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1914593117
关键词
intraneuronal A beta; neuronal inflammation; preplaque pathology; Alzheimer's disease
资金
- Merck Canada
- Canadian Institutes of Health Research [PJT-364544, 2017-1.2.1-NKP-2017-00002]
- Fonds de recherche du Quebec-Sante
- Rotary Foundation Global Grant Scholarship
Chronic inflammation during Alzheimer's disease (AD) is most often attributed to sustained microglial activation in response to amyloid-beta (A beta) plaque deposits and cell death. However, cytokine release and microgliosis are consistently observed in AD transgenic animal models devoid of such pathologies, bringing into question the underlying processes that may be at play during the earliest AD-related immune response. We propose that this plaque-independent inflammatory reaction originates from neurons burdened with increasing levels of soluble and oligomeric A beta, which are known to be the most toxic amyloid species within the brain. Laser microdissected neurons extracted from preplaque amyloid precursor protein (APP) transgenic rats were found to produce a variety of potent immune factors, both at the transcript and protein levels. Neuron-derived cytokines correlated with the extent of microglial activation and mobilization, even in the absence of extracellular plaques and cell death. Importantly, we identified an inflammatory profile unique to A beta-burdened neurons, since neighboring glial cells did not express similar molecules. Moreover, we demonstrate within disease-vulnerable regions of the human brain that a neuron- specific inflammatory response may precede insoluble A beta plaque and tau tangle formation. Thus, we reveal the A beta-burdened neuron as a primary proinflammatory agent, implicating the intraneuronal accumulation of A beta as a significant immunological component in the AD pathogenesis.
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