Early intraneuronal amyloid triggers neuron-derived inflammatory signaling in APP transgenic rats and human brain

Lindsay A. Welikovitch, Sonia Do Carmo, Zsófia Maglóczky, Janice C. Malcolm, János Loke, William L. Klein, Tamás Freund, A. Claudio Cuello*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

61 Scopus citations


Chronic inflammation during Alzheimer's disease (AD) is most often attributed to sustained microglial activation in response to amyloid-β (Aβ) 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 Aβ, 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 Aβ-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 Aβ plaque and tau tangle formation. Thus, we reveal the Aβ-burdened neuron as a primary proinflammatory agent, implicating the intraneuronal accumulation of Aβ as a significant immunological component in the AD pathogenesis.

Original languageEnglish (US)
Pages (from-to)6844-6854
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number12
StatePublished - Mar 24 2020


  • Alzheimer's disease
  • Intraneuronal Aβ
  • Neuronal inflammation
  • Preplaque pathology

ASJC Scopus subject areas

  • General


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