Microglia in Alzheimer’s Disease: Activated, Dysfunctional or Degenerative

Abstract

Microglial activation has been considered a crucial player in the pathological process of multiple human neurodegenerative diseases. In some of these pathologies, such as Amyotrophic Lateral Sclerosis or Multiple Sclerosis, the immune system and microglial cells (as part of the cerebral immunity) play a central role. In other degenerative processes, such as Alzheimer’s disease (AD), the role of microglia is far to be elucidated. In this “mini-review” article, we briefly highlight our recent data comparing the microglial response between amyloidogenic transgenic models, such as APP/PS1 and AD patients. Since the AD pathology could display regional heterogeneity, we focus our work at the hippocampal formation. In APP based models a prominent microglial response is triggered around amyloid-beta (Aβ) plaques. These strongly activated microglial cells could drive the AD pathology and, in consequence, could be implicated in the neurodegenerative process observed in models. On the contrary, the microglial response in human samples is, at least, partial or attenuated. This patent difference could simply reflect the lower and probably slower Aβ production observed in human hippocampal samples, in comparison with models, or could reflect the consequence of a chronic long-standing microglial activation. Beside this differential response, we also observed microglial degeneration in Braak V–VI individuals that, indeed, could compromise their normal role of surveying the brain environment and respond to the damage. This microglial degeneration, particularly relevant at the dentate gyrus, might be mediated by the accumulation of toxic soluble phospho-tau species. The consequences of this probably deficient immunological protection, observed in AD patients, are unknown.

Microglial activation occurs late during preclinical Alzheimer's disease

“…In contrast to this hypothesis, we have previously reported that widespread NFD in advanced AD (NFT Stages V–VI) is not accompanied by the presence of activated microglia but, instead, by the presence of dystrophic microglia (Streit, Braak, Xue, & Bechmann, ), cells exhibiting morphological features indicative of cellular senescence (Streit, Sammons, Kuhns, & Sparks, ). Thus, unlike what is reported in transgenic mouse models, microglial activation does not seem to be part of late‐stage AD in humans (Navarro et al, ) which is why, in this study, we have focused our histopathological evaluation on earlier disease stages in nondemented subjects to determine the onset of microglial activation during preclinical evolution of LOAD. This idea is in line with some authors' suggestions that neuroinflammation begins early during AD pathogenesis (Cribbs et al, ; Hoozemans, Veerhuis, Rozemuller, & Eikelenboom, ) and wanes in older patients (Hoozemans, Rozemuller, van Haastert, Eikelenboom, & van Gool, ).…”

Dystrophic microglia in late‐onset Alzheimer's disease

“…Even if some of the mouse models did develop microglial dystrophy, it would only be momentary because the young mice would be able to quickly replace degenerated microglia with new ones, as suggested by the stroke findings mentioned above (Figure ). The microglial response to amyloid also seems to be much stronger in mice than in humans (Navarro et al, ), speaking to the existence of a robust and vital microglial population in these animals and standing in stark contrast to the fragility of microglia that exist in aged human brains. Lastly, as discussed before (Streit et al, ), it is obvious that mice simply do not live long enough to develop neuronal and glial degeneration in the same way humans do, and are therefore unlikely to ever yield authentic AD models.…”

Microglia and the aging brain: are senescent microglia the key to neurodegeneration?

“…This is because activated microglia have been found in association with disease markers such as plaques of β‐amyloid in AD (Mattiace et al ). However, there has been recent discussion as to whether these microglia are activated or dystrophic and which form is mostly likely to be causative in the relevant pathological changes (Navarro et al ). Even considering a possible activated state, evidence suggest that both markers of M1 and M2 activation states are present in AD (Hopperton et al ).…”