Novel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology

Sierksma, Annerieke; Lu, Ashley; Mancuso, Renzo; Fattorelli, Nicola; Thrupp, Nicola; Salta, Evgenia; Zoco, Jesus; Blum, David; Buée, Luc; Strooper, Bart De; Fiers, Mark

doi:10.15252/emmm.201910606

Cited by 185 publications

(130 citation statements)

References 78 publications

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“…The PRS approach could be a robust tool to predict the risk and the age of onset of AD. The latest studies on two AD mouse models demonstrate that microglia play a key role in AD pathogenesis, and AD risk genes converge to microglia [213]. If microglia were exposed to Aβ, novel genes have been significantly upregulated and expressed and, as a result, the microglia switched to an activated status.…”

Section: Genetic Risk Factors Of Ad: Classical Studies and Novel Resultsmentioning

confidence: 99%

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

2020

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The structural polymorphism and the physiological and pathophysiological roles of two important proteins, β-amyloid (Aβ) and tau, that play a key role in Alzheimer’s disease (AD) are reviewed. Recent results demonstrate that monomeric Aβ has important physiological functions. Toxic oligomeric Aβ assemblies (AβOs) may play a decisive role in AD pathogenesis. The polymorph fibrillar Aβ (fAβ) form has a very ordered cross-β structure and is assumed to be non-toxic. Tau monomers also have several important physiological actions; however, their oligomerization leads to toxic oligomers (TauOs). Further polymerization results in probably non-toxic fibrillar structures, among others neurofibrillary tangles (NFTs). Their structure was determined by cryo-electron microscopy at atomic level. Both AβOs and TauOs may initiate neurodegenerative processes, and their interactions and crosstalk determine the pathophysiological changes in AD. TauOs (perhaps also AβO) have prionoid character, and they may be responsible for cell-to-cell spreading of the disease. Both extra- and intracellular AβOs and TauOs (and not the previously hypothesized amyloid plaques and NFTs) may represent the novel targets of AD drug research.

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Section: Genetic Risk Factors Of Ad: Classical Studies and Novel Resultsmentioning

confidence: 99%

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

2020

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“…This was opposite in hyper-homeostatic microglia. Interestingly, HEXB has been previously associated with microglia responses in AD 35 , and is responsible for production of two enzymes, beta-hexosaminidase A and B that play a critical role in lysosomal degradation of sphingolipids. Loss of HEXB is associated with Sandhoff disease, a rare disorder that leads to progressive neurodegeneration of the brain and spinal cord.…”

Section: Discussionmentioning

confidence: 99%

“…DAM populations in our wild-derived and B6 AD panel were also significantly smaller than has been previously reported in another amyloid strain, B6. APP swe /PS1 L166P 35 which is also an aggressive amyloid strain with plaque accumulation being observed as early as 6 weeks 41…”

Section: Discussionmentioning

confidence: 99%

Natural genetic variation determines microglia heterogeneity in wild-derived mouse models of Alzheimer’s disease

Yang

Onos

Choi

et al. 2020

Preprint

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Microglia are now considered drivers of Alzheimer's disease (AD) pathology. However, single-cell RNA-sequencing (scRNA-seq) of microglia in mice, a key preclinical model organsim, have shown mixed results regarding translatability to human studies. To address this, scRNA-seq of microglia from C57BL/6J (B6) and wild-derived strains WSB/EiJ, CAST/EiJ and PWK/PhJ carrying APP/PS1 was performed and demonstrated that genetic diversity significantly altered features and dynamics of microglia in baseline neuroimmune functions and in response to amyloidosis. There was significant variation in abundance of microglial subpopulations, including numbers of disease-associated microglia and interferon-responding microglia across the strains.Further, for each subpopulation, significant gene expression differences were observed between strains, and relative to B6 that included nineteen genes previously associated with human AD including Apoe, Trem2, Bin1 and Sorl1. This resource will be critical in the development of appropriately targeted therapeutics for AD and a range of other neurological diseases. 30 Introduction 31Alzheimer's disease (AD) is defined by the neuropathological accumulation of beta 32 amyloid plaques, neurofibrillary tangles of tau and widespread neuronal loss. AD is the 33 most common cause of adult dementia and is characterized by a wide range of 34 cognitive and behavioral deficits that severely impact quality of life and the ability to self-35 care. Recent work has re-focused the field towards the contribution of brain glial cells to 36 the initiation and spread of these disease-specific pathologies, and specifically on the 37 role of microglia as potentially a causative cell type in driving disease development and 38 progression. Human genome-wide association studies (GWAS) have identified more 39 than 25 variants near genes uniquely expressed in microglia that are predicted to 40 increase susceptibility for AD. In light of this complexity, the mouse represents a critical 41 model system to dissect the role of microglia and other glia in AD. 42 43There has been large debate regarding the alignment of mouse microglia to human 44 microglia in terms of identity, diversity and function. With the more widespread use of 45 single-cell sequencing technology, a number of groups have suggested that the species 46 difference is too great for conclusions drawn from mouse models to inform our 47 understanding of human microglia1,2. Central to this argument is the discovery and 48 description of a specific class of microglia in the mouse, disease-associated microglia 49 (DAM)3. Based upon the current data it is unclear whether the presence or absence of 50 DAM in human AD patients is the result of differences in tissue collection, extraction of 51 cells, genetic diversity of patients, sub-type of AD presented in donors or even the 52 relevant disease1,4. Recent work has demonstrated that single-nucleus RNA 53 sequencing of stored human tissue fails to detect differences in microglia activation 54 between AD and contro...

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“…The different (Abelson interactor family protein 3) which are genes mainly or exclusively expressed in myeloid cells, also point into that direction (15). Many of the risk genes of AD become upregulated in microglia when exposed to Aβ but less so to TAU pathology (34). Thus, a large part of the genetic risk of AD, as opposed to genetic cause of AD, seems to converge into the microglial response to amyloid plaques.…”

Section: Causal High Risk and Protective Variants Are Involved In Apmentioning

confidence: 99%

“…The genetics also strongly imply microglia responses to amyloid plaques in AD. Assuming that these responses are directed by the genetic risk profile of the patient, one would predict that some patients are protected from the damage caused by amyloid plaques because of their excellent microglia (34)…”

Section: Causal High Risk and Protective Variants Are Involved In Apmentioning

confidence: 99%

Translating genetic risk of Alzheimer’s disease into mechanistic insight and drug targets

Sierksma

Escott‐Price

Strooper

2020

Science

Self Cite

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To provide better prevention and treatment, we need to understand the environmental and genetic risks of Alzheimer’s disease (AD). However, the definition of AD has been confounded with dementia in many studies. Thus, overinterpretation of genetic findings with regard to mechanisms and drug targets may explain, in part, controversies in the field. Here, we analyze the different forms of genetic risk of AD and how these can be used to model disease. We stress the importance of studying gene variants in the right cell types and in the right pathological context. The lack of mechanistic understanding of genetic variation has become the major bottleneck in the search for new drug targets for AD.

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Novel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology

Cited by 185 publications

References 78 publications

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

Natural genetic variation determines microglia heterogeneity in wild-derived mouse models of Alzheimer’s disease

Translating genetic risk of Alzheimer’s disease into mechanistic insight and drug targets

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