scholarly journals CD33M inhibits microglial phagocytosis, migration and proliferation, but the Alzheimer’s disease‐protective variant CD33m stimulates phagocytosis and proliferation, and inhibits adhesion

2021 ◽  
Author(s):  
Claire Ann Butler ◽  
Peter Thornton ◽  
Guy Charles Brown
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Microglial Phagocytosis ◽  
Protective Variant

scholarly journals N,N′-Diacetyl-p-phenylenediamine restores microglial phagocytosis and improves cognitive defects in Alzheimer’s disease transgenic mice

2019 ◽  
Vol 116 (47) ◽  
pp. 23426-23436 ◽  
Author(s):  
Min Hee Park ◽  
Misun Lee ◽  
Geewoo Nam ◽  
Mingeun Kim ◽  
Juhye Kang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Amyloid Β ◽  
Causative Factor ◽  
Central Feature ◽  
Microglial Phagocytosis ◽  
Cognitive Defects

As a central feature of neuroinflammation, microglial dysfunction has been increasingly considered a causative factor of neurodegeneration implicating an intertwined pathology with amyloidogenic proteins. Herein, we report the smallest synthetic molecule (N,N′-diacetyl-p-phenylenediamine [DAPPD]), simply composed of a benzene ring with 2 acetamide groups at the para position, known to date as a chemical reagent that is able to promote the phagocytic aptitude of microglia and subsequently ameliorate cognitive defects. Based on our mechanistic investigations in vitro and in vivo, 1) the capability of DAPPD to restore microglial phagocytosis is responsible for diminishing the accumulation of amyloid-β (Aβ) species and significantly improving cognitive function in the brains of 2 types of Alzheimer’s disease (AD) transgenic mice, and 2) the rectification of microglial function by DAPPD is a result of its ability to suppress the expression of NLRP3 inflammasome-associated proteins through its impact on the NF-κB pathway. Overall, our in vitro and in vivo investigations on efficacies and molecular-level mechanisms demonstrate the ability of DAPPD to regulate microglial function, suppress neuroinflammation, foster cerebral Aβ clearance, and attenuate cognitive deficits in AD transgenic mouse models. Discovery of such antineuroinflammatory compounds signifies the potential in discovering effective therapeutic molecules against AD-associated neurodegeneration.

scholarly journals The Alzheimer’s disease-associated protective Plcγ2-P522R variant promotes immune functions

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Mari Takalo ◽  
Rebekka Wittrahm ◽  
Benedikt Wefers ◽  
Samira Parhizkar ◽  
Kimmo Jokivarsi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Cell ◽  
Therapeutic Option ◽  
Immune Functions ◽  
Disease Etiology ◽  
Cell Functions ◽  
Bv2 Microglia ◽  
Brain Mrna ◽  
Protective Variant

Abstract Background Microglia-specific genetic variants are enriched in several neurodegenerative diseases, including Alzheimer’s disease (AD), implicating a central role for alterations of the innate immune system in the disease etiology. A rare coding variant in the PLCG2 gene (rs72824905, p.P522R) expressed in myeloid lineage cells was recently identified and shown to reduce the risk for AD. Methods To assess the role of the protective variant in the context of immune cell functions, we generated a Plcγ2-P522R knock-in (KI) mouse model using CRISPR/Cas9 gene editing. Results Functional analyses of macrophages derived from homozygous KI mice and wild type (WT) littermates revealed that the P522R variant potentiates the primary function of Plcγ2 as a Pip2-metabolizing enzyme. This was associated with improved survival and increased acute inflammatory response of the KI macrophages. Enhanced phagocytosis was observed in mouse BV2 microglia-like cells overexpressing human PLCγ2-P522R, but not in PLCγ2-WT expressing cells. Immunohistochemical analyses did not reveal changes in the number or morphology of microglia in the cortex of Plcγ2-P522R KI mice. However, the brain mRNA signature together with microglia-related PET imaging suggested enhanced microglial functions in Plcγ2-P522R KI mice. Conclusion The AD-associated protective Plcγ2-P522R variant promotes protective functions associated with TREM2 signaling. Our findings provide further support for the idea that pharmacological modulation of microglia via TREM2-PLCγ2 pathway-dependent stimulation may be a novel therapeutic option for the treatment of AD.

scholarly journals Microglial phagocytosis induced by fibrillar β-amyloid is attenuated by oligomeric β-amyloid: implications for Alzheimer's disease

2011 ◽  
Vol 6 (1) ◽  
pp. 45 ◽  
Author(s):  
Xiao-dong Pan ◽  
Yuan-gui Zhu ◽  
Nan Lin ◽  
Jing Zhang ◽  
Qin-yong Ye ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Microglial Phagocytosis ◽  
Β Amyloid

scholarly journals PIP2 depletion and altered endocytosis caused by expression of Alzheimer's disease‐protective variant PLCγ2 R522

2021 ◽  
Author(s):  
Emily Maguire ◽  
Georgina E Menzies ◽  
Thomas Phillips ◽  
Michael Sasner ◽  
Harriet M Williams ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protective Variant

Microglial Phagocytosis: A Disease-Associated Process Emerging from Alzheimer’s Disease Genetics

2020 ◽  
Vol 43 (12) ◽  
pp. 965-979
Author(s):  
Anna Podleśny-Drabiniok ◽  
Edoardo Marcora ◽  
Alison M. Goate
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Microglial Phagocytosis

scholarly journals NEUTROPHILS’ FUNCTIONAL STATE IN ALZHEIMER’S DISEASE

2019 ◽  
Vol 19 (1S) ◽  
pp. 81-82
Author(s):  
P A Ivanov ◽  
A A Shmakova ◽  
N M Mikhailova
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Functional State ◽  
Phagocytic Activity ◽  
Control Group ◽  
Amino Acid Residues ◽  
Activity Increase ◽  
Microglial Phagocytosis ◽  
Key Factor ◽  
Peripheral Markers

Alzheimer’s disease (AD) is the most widespread neurodegenerative disease of older age, which is associated with the deposition of amyloid-beta polymerized peptide (consisting of 42 amino-acid residues) in the brain. The microglial phagocytosis disturbance, which is observed during AD, is possibly the key factor in the process. The research of neutrophils in patients with AD is of special interest due to the pressing problem of finding peripheral markers of AD. Analysis of neutrophils’ functional state in patients with AD is the objective of the present study. A reliable decrease of neutrophils’ phagocytic activity was established in group of patients with AD in comparison with control group (p < 0,05) (PI = 1.16 [0.64; 2.68] and PI = 2.34 [2.06; 2.85], respectively). A reliable increase of leukocytic elastase (LE) enzymatic activity (p < 0.05) was discovered in neutrophil lysate in AD group compared to control (LE = 0.43 [0.29; 0.77] and 0.29 [0.26; 0.38], respectively) at the same time. Comparison of PI and LE indicators in neutrophils’ lysate of AD group showed negative correlation between these parameters (r = 0.49, p < 0.05), which means that phagocytosis reduction during AD is accompanied by simultaneous LE activity increase in lysate of these cells.The obtained results allow to draw a conclusion that neutrophils’ phagocytic activity decreases during AD. Thus, discovered changes in neutrophils’ functional state can be considered as a potential peripheral AD marker.

scholarly journals Astrocytes Regulate Microglial Phagocytosis of Senile Plaque Cores of Alzheimer's Disease

1998 ◽  
Vol 149 (2) ◽  
pp. 329-340 ◽  
Author(s):  
David A. DeWitt ◽  
George Perry ◽  
Mark Cohen ◽  
Catherine Doller ◽  
Jerry Silver
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaque ◽  
Microglial Phagocytosis
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