Early intraneuronal amyloid triggers neuron-derived inflammatory signaling in APP transgenic rats and human brain
Open Access
- 24 March 2020
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 117 (12), 6844-6854
- https://doi.org/10.1073/pnas.1914593117
Abstract
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.Funding Information
- Gouvernement du Canada | Canadian Institutes of Health Research (PJT-364544)
- National Research, Development and Innovation Office (2017-1.2.1-NKP-2017-00002)
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