Journal of Neuroinflammation最新文献

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid beta (Aβ) accumulation, tau pathology, and cognitive decline, with aging as the primary risk factor. To investigate whether age influences susceptibility to Aβ toxicity, we used a tetracycline-inducible mouse model expressing a mutant human APP transgene (APPSweInd) and initiated expression during either mid-age (6-18 months) or old age (12-24 months). After one year of transgene activation, we assessed behavior, amyloid pathology, inflammation, autophagy, and brain gene expression compared to age-matched controls. Although APP expression, Aβ deposition, inflammatory markers, and autophagic flux were comparable between age groups, aged APP-expressing mice displayed cognitive impairments, hyperactivity, and motor deficits that were absent in their younger counterparts. Transcriptomic analysis revealed selective downregulation of cholinergic system genes specifically in the aged APP-induced group, validated at RNA and protein levels. No changes were observed in markers of other neuronal cell types, indicating a targeted cholinergic vulnerability. These findings suggest that age enhances the brain's susceptibility to Aβ toxicity, particularly affecting the cholinergic system, rather than amplifying amyloid burden itself. This inducible model provides a relevant platform to study the interaction between aging and Aβ pathology and may help identify age-related factors contributing to AD progression.

Background: Cognitive dysfunction associated with type 1 diabetes (T1D) is closely linked to the accumulation of amyloid-beta (Aβ) oligomers. However, the role of microglia and their underlying molecular mechanisms in this process remain unclear. Triggering receptor expressed on myeloid cells 2 (TREM2), a microglial receptor critical for clearing neurotoxic Aβ and maintaining metabolic homeostasis, is dysfunctional in Alzheimer's disease. Here, we investigated TREM2-mediated microglial dysfunction in diabetic neurodegeneration.

Purpose: To investigate the role of TREM2-mediated microglial dysfunction in Aβ clearance and cognitive impairment in T1D.

Basic procedures: A total of 204 male C57BL/6J mice, aged 6-8 weeks, were used in this study. We performed single-nucleus RNA sequencing (snRNA-seq) on 59,356 cells from the prefrontal cortex and hippocampus. Aβ pathology was evaluated by western blot, immunofluorescence and ELISA. TREM2 knockout mice and the murine microglial cell line BV2 were used to study the role of TREM2 in cognitive function and Aβ clearance.

Main findings: T1D mice exhibited progressive memory deficits and prefrontal Aβ oligomer accumulation (36-50 kDa), with region-specific microglial activation. SnRNA-seq identified ten microglial subpopulations, with Trem2-enriched clusters (M1/M2/M3/M5) showing impaired phagocytosis and metabolic dysregulation. TREM2 knockout exacerbated cognitive deficits and Aβ accumulation in T1D mice. Mechanistically, TREM2 regulated microglial migration, phagocytosis of Aβ oligomers, and mitochondrial integrity under high-glucose conditions, potentially via the mTOR signaling pathway.

Principle conclusions: These findings establish TREM2 as a critical regulator of microglial Aβ clearance in T1D, operating mitochondrial and phagocytic programs via mTOR and highlighting its therapeutic potential for diabetic neurodegeneration.

Brain border-associated macrophages (BAMs) are resident immune cells at the border of the central nervous system (CNS), and their physiological functions and roles in neurological diseases have been widely reported. However, the specific mechanisms by which BAMs contribute to vascular cognitive impairment and dementia (VCID) remain unclear. This article systematically reviews the subsets, origin and differentiation, molecular markers of BAMs, and their research progress in various brain diseases such as hypertension, Alzheimer's disease (AD), and stroke. On this basis, this article deeply analyzes the potential hypotheses of BAMs' involvement in the pathogenesis of VCID, including their regulation of neurovascular unit (NVU) homeostasis, their core role in neuroimmune inflammation, their impact on the lipid metabolism pathways in the CNS, and their involvement in the pathogenesis of vascular risk factor-related cognitive impairment (VRFCI). The mechanistic hypotheses proposed in this article aim to provide new perspectives for understanding the pathophysiology of VCID and may open up new directions for the development of early intervention and targeted treatment strategies.

Microglial deformation and migration represent the final stages of inflammatory cytokines release, a key contributor to Alzheimer's disease (AD) pathology. However, the upstream regulators that initiate these morphological and functional changes in microglia remain unclear. In this study, we observed marked cytoskeletal reorganization in the hippocampal microglia of 2VO rats at 8 weeks, indicative of a shift from a homeostatic to a pro-inflammatory state. Notably, Tincr expression was significantly downregulated in both the microglia of 2VO rats and the hippocampi of AD patients. Tincr knockdown promoted microglial deformation and migration, accompanied by enhanced cytokines release and phagocytic capacity. These morphological changes correlated with redistribution of non-muscle myosin IIA ( NM IIA) and reduced expression of MYPT1, both in vitro and in vivo, effects that were reversed by Tincr overexpression. Genetic rescue of Mypt1 restored MYPT1 levels and attenuated Tincr-deficiency-induced microglial deformation in the hippocampi of 5xFAD mice. Mechanistically, Tincr enhanced MYPT1 protein expression through dual: functioning as a competing endogenous RNA (ceRNA) that sponged miR-153-3p, and serving as a direct protein-binding scaffold for MYPT1, thereby suppressing NM IIA phosphorylation and stabilizing microglial structure. These findings identify the Tincr-MYPT1-NM IIA axis as a critical regulatory pathway underlying chronic cerebral hypoperfusion (CCH)-induced microglial deformation and dysfunction, offering a novel mechanistic insight into the pathogenesis of neuroinflammation in AD.

Traumatic brain injury (TBI) frequently causes cognitive dysfunction, with astrocytes playing a pivotal role in its pathogenesis. ​Specifically,​​ TBI triggers excessive astrocyte reactivity, ​leading to a phagocytic phenotype in astrocytes that contributes to abnormal synaptic phagocytosis and cognitive decline. ​Sirtuin 1 (SIRT1) reduction was region-specific, with significant downregulation observed in the hippocampus and cortex, reflecting the selective vulnerability of these regions to TBI-induced pathology. Although​ SIRT1 ​is​ a neuroprotective deacetylase, its regulatory mechanism in post-TBI astrocyte phagocytosis remains unclear. This study elucidates the mechanism through which SIRT1 attenuates TBI-induced cognitive deficits, specifically by ​​promoting autophagic flux in astrocytes​​ and subsequently ​​suppressing MEGF10-mediated synaptic phagocytosis​​. The investigation leveraged a combination of clinical human samples and astrocyte-specific murine models, including SIRT1-overexpression and ATG7-knockdown systems. Crucially, ​​astrocyte-specific knockdown of ATG7​​ was employed to mechanistically demonstrate that the SIRT1-driven degradation of MEGF10 and the consequent synaptic preservation are ​​strictly dependent on a functional autophagy pathway​​, as evidenced by the complete abolition of SIRT1's beneficial effects upon ATG7 knockdown. ​Methodologies included​ Western blotting, immunofluorescence, behavioral tests (Barnes maze), and in vitro assays. Notably, TBI ​significantly​ reduced SIRT1 levels; astrocytic SIRT1 overexpression ​suppressed​ MEGF10 expression via ATG7-dependent autophagy, ​thereby​ alleviating astrogliosis, synaptic loss, and cognitive deficits. ​Critically, these protective effects were abrogated by​ ATG7 knockdown. ​Collectively, our results define​ the SIRT1-autophagy-MEGF10 axis ​as a key regulator​ of astrocytic phagocytosis, ​revealing​ a novel therapeutic target for injury-related cognitive dysfunction.