Human early-onset dementia caused by DAP12 deficiency reveals a unique signature of dysregulated microglia

Zhou, Yingyue; Tada, Mari; Cai, Zhongli; Andhey, Prabhakar S.; Swain, Amanda; Miller, Kelly R.; Gilfillan, Susan; Artyomov, Maxim N.; Takao, Masaki; Kakita, Akiyoshi; Colonna, Marco

doi:10.1038/s41590-022-01403-y

Cited by 27 publications

(20 citation statements)

References 63 publications

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“…S3F, Fig. S4F), which were also significantly upregulated in the NHD brain microglia according to a recent single nucleus RNA-sequencign (sn-RNAseq) analysis ( 22 ). Notably, these gene sets were upregulated in the NHD MDMi in all treatment conditions, suggesting a strong proinflammatory transcriptional profile in these cells even without an external stimulus.…”

Section: Resultsmentioning

confidence: 65%

MonoallelicTYROBPdeletion is a novel risk factor for Alzheimer’s disease

Martiskainen,

Willman,

Heikkinen

et al. 2024

Preprint

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Biallelic loss-of-function variants inTYROBPandTREM2cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some otherTREM2variants contribute to the risk of Alzheimer's disease (AD) and frontotemporal dementia, while deleteriousTYROBPvariants are globally extremely rare and their role in neurodegenerative diseases remains unclear. The population history of Finns has favored the enrichment of deleterious founder mutations, including a 5.2 kb deletion encompassing exons 1-4 ofTYROBPand causing NHD in homozygous carriers. We used here a proxy marker to identify monoallelicTYROBPdeletion carriers in the Finnish biobank study FinnGen combining genome and health registry data of 520,210 Finns. We show that monoallelicTYROBPdeletion associates with an increased risk and earlier onset age of AD and dementia when compared to noncarriers. In addition, we present the first reported case of a monoallelicTYROBPdeletion carrier with NHD-type bone cysts. Mechanistically, monoallelicTYROBPdeletion leads to decreased levels of DAP12 protein (encoded byTYROBP) in myeloid cells. Using transcriptomic and proteomic analyses of human monocyte-derived microglia-like cells, we show that upon lipopolysaccharide stimulation monoallelicTYROBPdeletion leads to the upregulation of the inflammatory response and downregulation of the unfolded protein response when compared to cells with two functional copies ofTYROBP. Collectively, our findings indicateTYROBPdeletion as a novel risk factor for AD and suggest specific pathways for therapeutic targeting.

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Section: Resultsmentioning

confidence: 65%

MonoallelicTYROBPdeletion is a novel risk factor for Alzheimer’s disease

Martiskainen,

Willman,

Heikkinen

et al. 2024

Preprint

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“…Human DAP12 loss-of-function variants cause Nasu-Hakola disease (NHD), which features cerebral atrophy, myelin loss, and gliosis [30][31][32]69 . However, mice lacking DAP12 signaling exhibit milder phenotypes, not fully resembling human NHD 70 . This divergence suggests that DAP12deficient mice may not be ideal for comprehensive NHD brain phenotype studies, emphasizing the need for specific insults to reveal DAP12 deficiency effects.…”

Section: Discussionmentioning

confidence: 99%

DAP12 deficiency alters microglia-oligodendrocyte communication and enhances resilience against tau toxicity

Chen,

Fan,

Guo

et al. 2023

Preprint

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Pathogenic tau accumulation fuels neurodegeneration in Alzheimer’s disease (AD). Enhancing aging brain’s resilience to tau pathology would lead to novel therapeutic strategies. DAP12 (DNAX-activation protein 12) is critically involved in microglial immune responses. Previous studies have showed that mice lacking DAP12 in tauopathy mice exhibit higher tau pathology but are protected from tau-induced cognitive deficits. However, the exact mechanism remains elusive. Our current study uncovers a novel resilience mechanism via microglial interaction with oligodendrocytes. Despite higher tau inclusions, Dap12 deletion curbs tau-induced brain inflammation and ameliorates myelin and synapse loss. Specifically, removal of Dap12 abolished tau-induced disease-associated clusters in microglia (MG) and intermediate oligodendrocytes (iOli), which are spatially correlated with tau pathology in AD brains. Our study highlights the critical role of interactions between microglia and oligodendrocytes in tau toxicity and DAP12 signaling as a promising target for enhancing resilience in AD.

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“…Systemic vascular health thus exerts its effects on the brain over decades rather than years, allowing a significant time period for prevention and treatment. Additionally, brain vascular cell abnormalities are increasingly recognized as early and important contributors to the pathophysiology of several neurodegenerative diseases, including AD, frontotemporal dementia, early-onset dementia and Huntington’s disease [ 23 , 24 , 25 , 26 ]. The relationship between systemic vascular health and brain health is likely mediated by mechanisms of resistance and resilience.…”

Section: Vascular Health For Reservementioning

confidence: 99%

Brain Vascular Health in ALS Is Mediated through Motor Cortex Microvascular Integrity

Schreiber

Bernal

Ulbrich

et al. 2023

Cells

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Brain vascular health appears to be critical for preventing the development of amyotrophic lateral sclerosis (ALS) and slowing its progression. ALS patients often demonstrate cardiovascular risk factors and commonly suffer from cerebrovascular disease, with evidence of pathological alterations in their small cerebral blood vessels. Impaired vascular brain health has detrimental effects on motor neurons: vascular endothelial growth factor levels are lowered in ALS, which can compromise endothelial cell formation and the integrity of the blood–brain barrier. Increased turnover of neurovascular unit cells precedes their senescence, which, together with pericyte alterations, further fosters the failure of toxic metabolite removal. We here provide a comprehensive overview of the pathogenesis of impaired brain vascular health in ALS and how novel magnetic resonance imaging techniques can aid its detection. In particular, we discuss vascular patterns of blood supply to the motor cortex with the number of branches from the anterior and middle cerebral arteries acting as a novel marker of resistance and resilience against downstream effects of vascular risk and events in ALS. We outline how certain interventions adapted to patient needs and capabilities have the potential to mechanistically target the brain microvasculature towards favorable motor cortex blood supply patterns. Through this strategy, we aim to guide novel approaches to ALS management and a better understanding of ALS pathophysiology.

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Human early-onset dementia caused by DAP12 deficiency reveals a unique signature of dysregulated microglia

Cited by 27 publications

References 63 publications

MonoallelicTYROBPdeletion is a novel risk factor for Alzheimer’s disease

MonoallelicTYROBPdeletion is a novel risk factor for Alzheimer’s disease

DAP12 deficiency alters microglia-oligodendrocyte communication and enhances resilience against tau toxicity

Brain Vascular Health in ALS Is Mediated through Motor Cortex Microvascular Integrity

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