Functional BRI2-TREM2 interactions in microglia: implications for Alzheimer’s and related dementias

Yin, Tao; Yesiltepe, Metin; D’Adamio, Luciano

doi:10.1038/s44319-024-00077-x

Cited by 4 publications

(2 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Notably, LPS stimulation has been shown to decrease TREM2 surface expression and increase sTREM2 release in RAW264.7 cells, highlighting its role in TREM2 shedding and sTREM2 generation ( Bandow et al, 2022 ). Additionally, BRI2 modulates sTREM2 functionality by inhibiting α-secretase-mediated cleavage of TREM2, affecting microglial phagocytic capabilities under pathological conditions ( Yin T. et al, 2024 ). VEGF is recognized as a pivotal regulator of microglial phagocytosis in AD, facilitating the cleavage and release of sTREM2, thus enhancing the clearance of Aβ oligomers ( de Gea et al, 2023 ).…”

Section: Regulatory Mechanisms Of Strem2 Shedding and Metabolic Degra...mentioning

confidence: 99%

“…These mutations are posited to diminish the receptor’s protective functions, especially concerning Aβ plaque management ( Condello et al, 2015 ; Yuan et al, 2016 ). Notably, a soluble variant of TREM2 (sTREM2) detected in cerebrospinal fluid (CSF) and plasma exhibits dynamic concentration changes through the AD continuum, with initial elevations during early symptomatic phases followed by reductions in later stages ( Piccio et al, 2008 , 2016 ; Heslegrave et al, 2016 ; Suárez-Calvet et al, 2016a , b ; Zhou W. et al, 2023 ; Yin T. et al, 2024 ). Elevated CSF sTREM2 levels correlate with attenuated cognitive decline and reduced cerebral atrophy in AD subjects ( Ewers et al, 2019 ), proposing sTREM2 as a potential biomarker for microglial activation and a moderator of disease trajectory ( Gu et al, 2023 ).…”

Section: Introduction: Unveiling the Role Of Strem2 In Alzheimer’s Di...mentioning

confidence: 99%

See 1 more Smart Citation

Decoding sTREM2: its impact on Alzheimer’s disease – a comprehensive review of mechanisms and implications

Lin,

Kong,

Chen

et al. 2024

Front. Aging Neurosci.

View full text Add to dashboard Cite

Soluble Triggering Receptor Expressed on Myeloid Cells 2 (sTREM2) plays a crucial role in the pathogenesis of Alzheimer’s disease (AD). This review comprehensively examines sTREM2’s involvement in AD, focusing on its regulatory functions in microglial responses, neuroinflammation, and interactions with key pathological processes. We discuss the dynamic changes in sTREM2 levels in cerebrospinal fluid and plasma throughout AD progression, highlighting its potential as a therapeutic target. Furthermore, we explore the impact of genetic variants on sTREM2 expression and its interplay with other AD risk genes. The evidence presented in this review suggests that modulating sTREM2 activity could influence AD trajectory, making it a promising avenue for future research and drug development. By providing a holistic understanding of sTREM2’s multifaceted role in AD, this review aims to guide future studies and inspire novel therapeutic strategies.

show abstract

Section: Regulatory Mechanisms Of Strem2 Shedding and Metabolic Degra...mentioning

confidence: 99%

Section: Introduction: Unveiling the Role Of Strem2 In Alzheimer’s Di...mentioning

confidence: 99%

Decoding sTREM2: its impact on Alzheimer’s disease – a comprehensive review of mechanisms and implications

Lin,

Kong,

Chen

et al. 2024

Front. Aging Neurosci.

View full text Add to dashboard Cite

show abstract

Microglia contribute to the production of the amyloidogenic ABri peptide in familial British dementia

Arber,

Casey,

Crawford

et al. 2024

Acta Neuropathol

View full text Add to dashboard Cite

Mutations in ITM2B cause familial British, Danish, Chinese, and Korean dementias. In familial British dementia (FBD), a mutation in the stop codon of the ITM2B gene (also known as BRI2) causes a C-terminal cleavage fragment of the ITM2B/BRI2 protein to be extended by 11 amino acids. This fragment, termed amyloid-Bri (ABri), is highly insoluble and forms extracellular plaques in the brain. ABri plaques are accompanied by tau pathology, neuronal cell death and progressive dementia, with striking parallels to the aetiology and pathogenesis of Alzheimer’s disease. The molecular mechanisms underpinning FBD are ill-defined. Using patient-derived induced pluripotent stem cells, we show that expression of ITM2B/BRI2 is 34-fold higher in microglia than neurons and 15-fold higher in microglia compared with astrocytes. This cell-specific enrichment is supported by expression data from both mouse and human brain tissue. ITM2B/BRI2 protein levels are higher in iPSC-microglia compared with neurons and astrocytes. The ABri peptide was detected in patient iPSC-derived microglial lysates and conditioned media but was undetectable in patient-derived neurons and control microglia. The pathological examination of post-mortem tissue supports the presence of ABri in microglia that are in proximity to pre-amyloid deposits. Finally, gene co-expression analysis supports a role for ITM2B/BRI2 in disease-associated microglial responses. These data demonstrate that microglia are major contributors to the production of amyloid forming peptides in FBD, potentially acting as instigators of neurodegeneration. Additionally, these data also suggest ITM2B/BRI2 may be part of a microglial response to disease, motivating further investigations of its role in microglial activation. These data have implications for our understanding of the role of microglia and the innate immune response in the pathogenesis of FBD and other neurodegenerative dementias including Alzheimer’s disease.

show abstract

Intravenous chaperone treatment of late-stage Alzheimer´s disease (AD) mouse model affects amyloid plaque load, reactive gliosis and AD-related genes

Zhang,

Ohshima,

Brodin

et al. 2024

Transl Psychiatry

View full text Add to dashboard Cite

Treatment strategies that are efficient against established Alzheimer’s disease (AD) are needed. BRICHOS is a molecular chaperone domain that prevents amyloid fibril formation and associated cellular toxicity. In this study, we treated an AD mouse model seven months after pathology onset, using intravenous administration of recombinant human (rh) Bri2 BRICHOS R221E. Two injections of rh Bri2 BRICHOS R221E per week for three months in AD mice reduced amyloid β (Aβ) burden, and mitigated astro- and microgliosis, as determined by glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba1) immunohistochemistry. Sequencing of RNA from cortical microglia cells showed that BRICHOS treatment normalized the expression of identified plaque-induced genes in mice and humans, including clusterin and GFAP. Rh Bri2 BRICHOS R221E passed the blood–brain barrier (BBB) in age-matched wild-type mice as efficiently as in the AD mice, but then had no effect on measures of AD-like pathology, and mainly affected the expression of genes that affect cellular shape and movement. These results indicate a potential of rh Bri2 BRICHOS against advanced AD and underscore the ability of BRICHOS to target amyloid-induced pathology.

show abstract

Functional BRI2-TREM2 interactions in microglia: implications for Alzheimer’s and related dementias

Cited by 4 publications

References 63 publications

Decoding sTREM2: its impact on Alzheimer’s disease – a comprehensive review of mechanisms and implications

Decoding sTREM2: its impact on Alzheimer’s disease – a comprehensive review of mechanisms and implications

Microglia contribute to the production of the amyloidogenic ABri peptide in familial British dementia

Intravenous chaperone treatment of late-stage Alzheimer´s disease (AD) mouse model affects amyloid plaque load, reactive gliosis and AD-related genes

Contact Info

Product

Resources

About