The dense-core plaques of Alzheimer’s disease are granulomas

Abstract

Dense-core plaques, whose centers contain highly polymerized and compacted aggregates of amyloid β peptides, are one of the two defining histopathological features of Alzheimer’s disease. Recent findings indicate that these plaques do not form spontaneously but are instead constructed by microglia, the tissue macrophages of the central nervous system. We discuss cellular, structural, functional, and gene expression criteria by which the microglial assembly of dense-core plaques in the Alzheimer’s brain parallels the construction of granulomas by macrophages in other settings. We compare the genesis of these plaques to the macrophage assembly of mycobacterial granulomas, the defining histopathological features of tuberculosis. We suggest that if dense-core plaques are indeed granulomas, their simple disassembly may be contraindicated as an Alzheimer’s therapy.

Age-Related Oxidative Redox and Metabolic Changes Precede Intraneuronal Amyloid-β Accumulation and Plaque Deposition in a Transgenic Alzheimer’s Disease Mouse Model

“…Interestingly, the same early ablation of microglia in tau transgenic mice also inhibits the ApoE4-dependent accumulation of aggregated and hyperphosphorylated tau, suggesting that they may share upstream signaling pathways for accumulation [ 70 ]. Overall, the literature seems to be exposing a shift in pathogenic mechanism from Aβ secretion causing plaques, to metabolic and redox modulation that increases iAβ, which upon cellular death or damage releases iAβ into the parenchyma as neuritic plaques to spread cellular damage, including uptake by microglia and concentration into dense core plaque deposits [ 71 ].…”

Syk inhibitors protect against microglia-mediated neuronal loss in culture

“…Microglia are resident macrophages of the central nervous system (CNS) and are increasingly implicated in brain pathologies such as Alzheimer’s disease (AD), Parkinson’s disease, stroke, brain trauma, schizophrenia, autism, retinal and spinal pathology, as well as brain ageing ( Colonna and Butovsky, 2017 ; Qin et al, 2019 ; Greenhalgh et al, 2020 ; Kwon and Koh, 2020 ; Blaylock and Faria, 2021 ). These dynamic cells carry out disease-modifying functions, including: phagocytosis, degradation, and compaction of amyloid plaques ( Fu et al, 2012 ; Condello et al, 2015 ; Yuan et al, 2016 ; Feng et al, 2020 ; Huang et al, 2021 ; Lemke and Huang, 2022 ); regulation of inflammatory states ( Heneka et al, 2013 ); phagocytosis of synapses ( Stevens et al, 2007 ; Schafer et al, 2012 ; Hong et al, 2016 ); phagocytosis of dead cells and debris ( Sierra et al, 2010 ; Anderson et al, 2022 ); phagocytosis of stressed neurons ( Fricker et al, 2012a , b ); and recruiting peripheral immune cells to the brain ( Zhang et al, 2022 ). Thus, it is important to better understand the intracellular signalling pathways controlling these contrasting functions of microglia.…”

Oxytocin attenuates microglial activation and restores social and non-social memory in APP/PS1 Alzheimer model mice

“…Huang and collaborators (2021) recently reported results suggesting that microglia act as “trash compactors” and promote dense core plaque formation, 25 a mechanism that could decrease soluble Aβ levels and be neuroprotective in AD. 26 , 27 This prompted us to evaluate Aβ immunoreactivities within plaque cores. For this analysis, we calculated core density as the ratio of 6E10 immunoreactivity per unit area in plaques presenting a dense core (defined as core 6E10 immunoreactivity/area ratio greater than 35 arbitrary units).…”