Microglia phenotypes are associated with subregional patterns of concomitant tau, amyloid-β and α-synuclein pathologies in the hippocampus of patients with Alzheimer’s disease and dementia with Lewy bodies

Abstract

The cellular alterations of the hippocampus lead to memory decline, a shared symptom between Alzheimer’s disease (AD) and dementia with Lewy Bodies (DLB) patients. However, the subregional deterioration pattern of the hippocampus differs between AD and DLB with the CA1 subfield being more severely affected in AD. The activation of microglia, the brain immune cells, could play a role in its selective volume loss. How subregional microglia populations vary within AD or DLB and across these conditions remains poorly understood. Furthermore, how the nature of the hippocampal local pathological imprint is associated with microglia responses needs to be elucidated. To this purpose, we employed an automated pipeline for analysis of 3D confocal microscopy images to assess CA1, CA3 and DG/CA4 subfields microglia responses in post-mortem hippocampal samples from late-onset AD (n = 10), DLB (n = 8) and age-matched control (CTL) (n = 11) individuals. In parallel, we performed volumetric analyses of hyperphosphorylated tau (pTau), amyloid-β (Aβ) and phosphorylated α-synuclein (pSyn) loads. For each of the 32,447 extracted microglia, 16 morphological features were measured to classify them into seven distinct morphological clusters. Our results show similar alterations of microglial morphological features and clusters in AD and DLB, but with more prominent changes in AD. We identified two distinct microglia clusters enriched in disease conditions and particularly increased in CA1 and DG/CA4 of AD and CA3 of DLB. Our study confirms frequent concomitance of pTau, Aβ and pSyn loads across AD and DLB but reveals a specific subregional pattern for each type of pathology, along with a generally increased severity in AD. Furthermore, pTau and pSyn loads were highly correlated across subregions and conditions. We uncovered tight associations between microglial changes and the subfield pathological imprint. Our findings suggest that combinations and severity of subregional pTau, Aβ and pSyn pathologies transform local microglia phenotypic composition in the hippocampus. The high burdens of pTau and pSyn associated with increased microglial alterations could be a factor in CA1 vulnerability in AD.

Investigation of Inflammation in Lewy Body Dementia: A Systematic Scoping Review

“…Three decades after the publication of McGeer et al, several groups also used microglial morphological assessment to argue against the initial proposition that microglial activation is a hallmark of LBD neuropathology. Classification of activated microglia by visual confirmation of an ameboid state and increased staining of activation markers, such as CD68, found no increase in activated microglia in LBD brains and, interestingly, the presence of greater numbers of dystrophic microglia compared to age-matched controls [43][44][45][46][47]. A decreased phagocytic capacity of microglia has also been identified in the hippocampus of DLB and PD brains, along with an age-related decline in microglial function in all study groups, including controls [48].…”

The Intranigral Infusion of Human-Alpha Synuclein Oligomers Induces a Cognitive Impairment in Rats Associated with Changes in Neuronal Firing and Neuroinflammation in the Anterior Cingulate Cortex

“…While such heterogeneity is interesting in relation to the complex structure of the hippocampus and different roles of hippocampal subregions in memory processes, CA1 is one of the earliest sites within the hippocampus to be affected in PD-MCI patients [ 78 , 79 ]. The CA1 is also the most vulnerable subfield in AD, and CA1 microglia was more profoundly affected in AD [ 80 ]. Notably, the microglial production of the pro-inflammatory cytokine TNF-α was largely increased, suggesting that these cells acquired an altered phenotype in response to the infusion of H-αSynOs.…”

Phenomic Microglia Diversity as a Druggable Target in the Hippocampus in Neurodegenerative Diseases

“…Region-specific variations in gene expression (both increases and decreases) may be implicated in the progression or in the resolution of neurodegenerative diseases [201]. In the hippocampus of AD patients, the subregional pattern of atrophy is different from other groups of neurodegenerative conditions [203,204], and understanding the molecular and cellular mechanisms that lead to such a subregional vulnerability could unveil therapeutic strategies to alleviate the progression of memory decline. Genome-wide association studies (GWAS) identified AD onset risk loci that are associated with genes involved in microglia physiology and responses, such as CR1 (complement receptor type 1), SPI1 (transcription factor PU.1), TREM2 (triggering receptor expressed on myeloid cells 2), and CD33 [205].…”

“…In germ-free (GF) or specific pathogen-free (SPF) mice, the morphology of microglia is severely altered, and the cells have longer, very mobile, hyper-ramified projections (see an example in Figure 1H), which partially overlap in the spatial domains of neighboring microglia [206][207][208] entering into physical contact with the projections of adjacent cells. A possible functional consequence of these alterations of microglia projections is the altered In the hippocampus of AD patients, the subregional pattern of atrophy is different from other groups of neurodegenerative conditions [203,204], and understanding the molecular and cellular mechanisms that lead to such a subregional vulnerability could unveil therapeutic strategies to alleviate the progression of memory decline. Genome-wide association studies (GWAS) identified AD onset risk loci that are associated with genes involved in microglia physiology and responses, such as CR1 (complement receptor type 1), SPI1 (transcription factor PU.1), TREM2 (triggering receptor expressed on myeloid cells 2), and CD33 [205].…”