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

Abstract

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.

Osteopontin/secreted phosphoprotein-1 behaves as a molecular brake regulating the neuroinflammatory response to chronic viral infection

“…In this regard, a recent report describes low-level basal expression of TSPO in several regions of the brain including vascular endothelial cells and in Purkinje neurons in normal mouse brain compared to tissues from a TSPO knockout mouse [36]. Early intraneuronal accumulation of toxic amyloid in a mouse model of Alzheimer's disease was recently shown to initiate inflammatory gene expression of chemokines CCL2 and CCL3 in pyramidal neurons of the hippocampus, thus demonstrating that neurons have the capacity to initiate such signaling [54]. Clearly, additional studies are needed to have a more complete understanding of the neuroinflammatory response.…”

Identification of amyloid beta oligomers in locus coeruleus (LC) neurons of Alzheimer’s patients and their impact on LC oxidative stress, inhibitory neurotransmitter receptors and neuronal excitability

“…Neuroinflammation is considered a core component of Alzheimer’s pathology with both Aβ fibrils (Heneka et al 2015) and AβO mediating specific pathways (Welikovitch et al 2020). A distinctive feature of Alzheimer’s related neuroinflammation is the presence of activated microglia.…”

Osteopontin/Secreted Phosphoprotein-1 Behaves as a Molecular Brake Regulating the Brain Translocator Protein-Dependent Neuroinflammatory Response to Chronic Viral Infection

“…Moreover, TSPO can also be expressed in astrocytes, and these cells were not assessed in this study. Early intraneuronal accumulation of toxic amyloid in a mouse model of Alzheimer's disease was recently shown to initiate in ammatory gene expression of chemokines CCL2 and CCL3 in pyramidal neurons of the hippocampus, thus demonstrating that neurons have the capacity to initiate such signaling (49). Clearly, additional studies are needed to have a more complete understanding of the neuroin ammatory response.…”