Targeting microglia for the treatment of Alzheimer's Disease

Wes, Paul D.; Sayed, Faten A.; Bard, Frédérique; Gan, Li

doi:10.1002/glia.22988

Cited by 156 publications

(120 citation statements)

References 241 publications

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“…Reduced phagocytosis may be toxic to stressed neurons and indeed TREM2 activity has been positively associated with a neuroprotective microglial phenotype [39]. Modulating microglial activity through TREM2 has been proposed as a therapeutic target in Alzheimer’s disease [53]. Our data suggests that this therapeutic strategy may also be applicable in ALS.…”

Section: Discussionmentioning

confidence: 81%

A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis

Cooper‐Knock

Green

Altschuler

et al. 2017

acta neuropathol commun

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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that lacks a predictive and broadly applicable biomarker. Continued focus on mutation-specific upstream mechanisms has yet to predict disease progression in the clinic. Utilising cellular pathology common to the majority of ALS patients, we implemented an objective transcriptome-driven approach to develop noninvasive prognostic biomarkers for disease progression. Genes expressed in laser captured motor neurons in direct correlation (Spearman rank correlation, p < 0.01) with counts of neuropathology were developed into co-expression network modules. Screening modules using three gene sets representing rate of disease progression and upstream genetic association with ALS led to the prioritisation of a single module enriched for immune response to motor neuron degeneration. Genes in the network module are important for microglial activation and predict disease progression in genetically heterogeneous ALS cohorts: Expression of three genes in peripheral lymphocytes - LILRA2, ITGB2 and CEBPD – differentiate patients with rapid and slowly progressive disease, suggesting promise as a blood-derived biomarker. TREM2 is a member of the network module and the level of soluble TREM2 protein in cerebrospinal fluid is shown to predict survival when measured in late stage disease (Spearman rank correlation, p = 0.01). Our data-driven systems approach has, for the first time, directly linked microglia to the development of motor neuron pathology. LILRA2, ITGB2 and CEBPD represent peripherally accessible candidate biomarkers and TREM2 provides a broadly applicable therapeutic target for ALS.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0424-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 81%

A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis

Cooper‐Knock

Green

Altschuler

et al. 2017

acta neuropathol commun

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“…Neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease are associated with neuroinflammation (Ransohoff, 2016) and microglia appear to be central (Saijo and Glass, 2011; Joers et al, 2016; Wes et al, 2016). P2X4 and the related purinergic channel P2X7 (Bhattacharya and Biber, 2016) are involved in the regulation of microglial pathways therefore may also play roles in exacerbating inflammation in the CNS.…”

Section: Neuroinflammatory Disordersmentioning

confidence: 99%

P2X4 Receptor Function in the Nervous System and Current Breakthroughs in Pharmacology

et al. 2017

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Adenosine 5′-triphosphate is a well-known extracellular signaling molecule and neurotransmitter known to activate purinergic P2X receptors. Information has been elucidated about the structure and gating of P2X channels following the determination of the crystal structure of P2X4 (zebrafish), however, there is still much to discover regarding the role of this receptor in the central nervous system (CNS). In this review we provide an overview of what is known about P2X4 expression in the CNS and discuss evidence for pathophysiological roles in neuroinflammation and neuropathic pain. Recent advances in the development of pharmacological tools including selective antagonists (5-BDBD, PSB-12062, BX430) and positive modulators (ivermectin, avermectins, divalent cations) of P2X4 will be discussed.

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“…Antibodies can be engineered to eliminate the potential antibody-dependent cell killing, e.g., using IgG4 isotype to eliminate or limit binding to Fc receptors or removing Fc-mediated effects through methods such as mutating the binding site for Fc receptors [28]. Particularly, an approach that can shuttle CD33 antibody across the BBB may provide a solution to both brain penetration and the potential toxic cross-reactivity in the periphery; however, this method has not been shown to be a success in clinic studies [34]. Since CD33 has a strong species specificity, while work with human in vitro systems to study biology and intervention is feasible, humanized CD33 mice will be a necessary tool for target engagement confirmation, in vivo preclinical proof of concept studies, and pharmacokinetics and toxicology evaluation.…”

Section: Targeting Cd33 Through Other Approachesmentioning

confidence: 99%

“…The sialic acid ligand binding region is very flat and does not contain any binding pockets. Additionally, this region is highly polar, and polar small binding molecules are unlikely to get into the brain [24,25,34]. As a result, target-DOI: 10.1159/000492596 ing to CD33 should not be only restricted to the sialic acid binding domain and should also attempt to allosteric sites such as other regions in the V domain or regions between the C2 and V domains.…”

Section: Targeting Cd33 Through Small Moleculesmentioning

confidence: 99%

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CD33 in Alzheimer’s Disease – Biology, Pathogenesis, and Therapeutics: A Mini-Review

Zhao

2018

Gerontology

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Alzheimer’s disease (AD) affects nearly 50 million people worldwide, and currently no disease-modifying treatment is available. With continuous failure of anti-amyloid-beta- or tau-based therapies, identification of new targets has become an urgent necessity for AD prevention and therapy. Recently, conventional genetic approaches and computational strategies have converged on immune-inflammatory pathways as key events in the pathogenesis of AD. A number of genes have been highly linked to the onset and development of late-onset sporadic AD, the most common form of AD. Strikingly, most of these genes are involved in microglial biology. Mutations and/or differential expression of microglial receptors such as TREM2, CD33, and CR3 have been strongly associated with an increased risk of developing AD. The mechanistic actions of these risk factors in AD etiology have been actively investigated since they were identified. Whether these genes can be targeted for a disease-modifying treatment is under hot debate. CD33 is one of the top-ranked AD risk genes identified by genome-wide association studies. This review summarizes the recently advanced biology of CD33 and its association with AD. It also provides insights from a drug discovery perspective into the druggability, therapeutic strategies, and challenges to target CD33 for treating this devastating disorder.

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Targeting microglia for the treatment of Alzheimer's Disease

Cited by 156 publications

References 241 publications

A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis

A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis

P2X4 Receptor Function in the Nervous System and Current Breakthroughs in Pharmacology

CD33 in Alzheimer’s Disease – Biology, Pathogenesis, and Therapeutics: A Mini-Review

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