Microglia-mediated neuroinflammation has been implicated in the pathogenesis of Alzheimer’s disease (AD). Although microglia in aging and neurodegenerative disease model mice show a loss of homeostatic phenotype and activation of disease-associated microglia (DAM), a correlation between those phenotypes and the degree of neuronal cell loss has not been clarified. In this study, we performed RNA sequencing of microglia isolated from three representative neurodegenerative mouse models, AppNL-G-F/NL-G-F with amyloid pathology, rTg4510 with tauopathy, and SOD1G93A with motor neuron disease by magnetic activated cell sorting. In parallel, gene expression patterns of the human precuneus with early Alzheimer’s change (n = 11) and control brain (n = 14) were also analyzed by RNA sequencing. We found that a substantial reduction of homeostatic microglial genes in rTg4510 and SOD1G93A microglia, whereas DAM genes were uniformly upregulated in all mouse models. The reduction of homeostatic microglial genes was correlated with the degree of neuronal cell loss. In human precuneus with early AD pathology, reduced expression of genes related to microglia- and oligodendrocyte-specific markers was observed, although the expression of DAM genes was not upregulated. Our results implicate a loss of homeostatic microglial function in the progression of AD and other neurodegenerative diseases. Moreover, analyses of human precuneus also suggest loss of microglia and oligodendrocyte functions induced by early amyloid pathology in human.

A homozygous mutation in the gene for sigma 1 receptor (Sig1R) is a cause of inherited juvenile amyotrophic lateral sclerosis (ALS16). Sig1R localizes to the mitochondria‐associated membrane (MAM), which is an interface of mitochondria and endoplasmic reticulum. However, the role of the MAM in ALS is not fully elucidated. Here, we identified a homozygous p.L95fs mutation of Sig1R as a novel cause of ALS16. ALS‐linked Sig1R variants were unstable and incapable of binding to inositol 1,4,5‐triphosphate receptor type 3 (IP 3R3). The onset of mutant Cu/Zn superoxide dismutase (SOD1)‐mediated ALS disease in mice was accelerated when Sig1R was deficient. Moreover, either deficiency of Sig1R or accumulation of mutant SOD1 induced MAM disruption, resulting in mislocalization of IP 3R3 from the MAM, calpain activation, and mitochondrial dysfunction. Our findings indicate that a loss of Sig1R function is causative for ALS16, and collapse of the MAM is a common pathomechanism in both Sig1R‐ and SOD1‐linked ALS. Furthermore, our discovery of the selective enrichment of IP 3R3 in motor neurons suggests that integrity of the MAM is crucial for the selective vulnerability in ALS.

Neuroinflammation, which includes both neuroprotective and neurotoxic reactions by activated glial cells and infiltrated immune cells, is involved in the pathomechanism of amyotrophic lateral sclerosis (ALS). However, the cytokines that regulate the neuroprotective inflammatory response in ALS are not clear. Here, we identify transforming growth factor-β1 (TGF-β1), which is upregulated in astrocytes of murine and human ALS, as a negative regulator of neuroprotective inflammatory response. We demonstrate that astrocyte-specific overproduction of TGF-β1 in SOD1(G93A) mice accelerates disease progression in a non-cell-autonomous manner, with reduced IGF-I production in deactivated microglia and fewer T cells with an IFN-γ-dominant milieu. Moreover, expression levels of endogenous TGF-β1 in SOD1(G93A) mice negatively correlate with lifespan. Furthermore, pharmacological administration of a TGF-β signaling inhibitor after disease onset extends survival time of SOD1(G93A) mice. These findings indicate that astrocytic TGF-β1 determines disease progression and is critical to the pathomechanism of ALS.