Innate Immune Cell Death in Neuroinflammation and Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder molecularly characterized by the formation of amyloid β (Aβ) plaques and type 2 microtubule-associated protein (Tau) abnormalities. Multiple studies have shown that many of the brain’s immunological cells, specifically microglia and astrocytes, are involved in AD pathogenesis. Cells of the innate immune system play an essential role in eliminating pathogens but also regulate brain homeostasis and AD. When activated, innate immune cells can cause programmed cell death through multiple pathways, including pyroptosis, apoptosis, necroptosis, and PANoptosis. The cell death often results in the release of proinflammatory cytokines that propagate the innate immune response and can eliminate Aβ plaques and aggregated Tau proteins. However, chronic neuroinflammation, which can result from cell death, has been linked to neurodegenerative diseases and can worsen AD. Therefore, the innate immune response must be tightly balanced to appropriately clear these AD-related structural abnormalities without inducing chronic neuroinflammation. In this review, we discuss neuroinflammation, innate immune responses, inflammatory cell death pathways, and cytokine secretion as they relate to AD. Therapeutic strategies targeting these innate immune cell death mechanisms will be critical to consider for future preventive or palliative treatments for AD.

Inflammasome activation in traumatic brain injury and Alzheimer's disease

“…The inflammasome has emerged in recent years as a key player in a number of CNS diseases and conditions, particularly AD. As noted, Aβ alters the cellular ionic balance in neurons, but acts as a DAMP in microglia and astrocytes (Figure 3) [49,69,82].…”

“…In the event of trauma or infection, astrocytes become activated (astrogliosis), as indicated by an increase of the cytoskeletal protein glial fibrillary acidic protein (GFAP), and like microglia, secrete numerous inflammatory products, including cytokines and chemokines such as IL-1β, TNF-α, growth factors and reactive oxygen species [46,48]. There are numerous triggers of astrogliosis such as DAMPs from damaged cells, cytokines from microglia, Aβ from neurons, albumin from BBB disruption, and synaptic glutamate and adenosine tri-phosphate (ATP), the exact nature of astrocytic activation is still not well understood [48,49].…”

“…Microglia scavenger receptors identify and mediate Aβ uptake, resulting in microglia activation and inflammatory cytokine release [69]. About 25% of genes associated with immunity alterations in AD are associated with microglia [49]. Genetic mutations, such as PSEN and TREM2 are thought to cause microglia to become dysfunctional, impacting microglial autophagy and lysosomal function [9,97].…”

“…Interestingly, Aβ deposition appears to precede tau pathology in AD, suggesting that pTau deposition may represent a downstream product of Aβ pathology [14,100]. Indeed, microglia and astrocytic activation, potentially from Aβ or other sources, is thought to encourage pTau formation through the release of inflammatory cytokines such as the inflammasome product IL-1β [49]. However, tau pathologies occur in human AD that are separate of Aβ, and human imaging and postmortem studies have demonstrated alterations in microglial inflammatory activity in patients with tau pathology without the presence of Aβ [107].…”

Distinct and Dynamic Transcriptome Adaptations of iPSC-Generated Astrocytes after Cytokine Stimulation

“…Although the viability controls run within the experimental time period (up to 72 h) did not indicate a significant cell loss, it is possible that ACs being continuously stimulated for even longer periods would eventually die. Indeed, cell death (apoptosis or pyroptosis) has been repeatedly described for continuously stimulated glia [ 74 ]. To visualize the response pattern of some individual transcripts, the top 20 DEGs of each treatment condition were selected and pooled.…”