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

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.

Download Full-text

The Alzheimer’s disease-associated protective Plcγ2-P522R variant promotes beneficial microglial functions

10.1101/2020.04.08.031567 ◽

2020 ◽

Author(s):

Mari Takalo ◽

Rebekka Wittrahm ◽

Benedikt Wefers ◽

Samira Parhizkar ◽

Kimmo Jokivarsi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Immune Cell ◽

Cellular Mechanisms ◽

Disease Etiology ◽

Cell Functions ◽

Bv2 Microglia ◽

Brain Mrna ◽

Metabolizing Enzyme ◽

Functional Analyses

AbstractBackgroundMicroglia-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) selectively expressed in microglia and macrophages was recently identified and shown to reduce the risk for AD.MethodsTo assess the role of this variant in the context of immune cell functions, we generated a Plcγ2-P522R knock-in (KI) mouse model using CRISPR/Cas9 gene editing.ResultsFunctional 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, enhanced phagocytic activity, and increased acute inflammatory response of the KI cells. Enhanced phagocytosis was also observed in mouse BV2 microglia-like cells overexpressing human PLCγ2-P522R, but not in PLCγ2-WT expressing cells. Furthermore, the brain mRNA signature together with microglia-specific PET imaging indicated microglia activation in Plcγ2-P522R KI mice.ConclusionThus, we have delineated cellular mechanisms of the protective Plcγ2-P522R variant, which provide further support for the emerging idea that activated microglia exert protective functions in AD.

Download Full-text

The Phosphoinositide Signal Transduction Pathway in the Pathogenesis of Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205014666170829100230 ◽

2018 ◽

Vol 15 (4) ◽

pp. 355-362 ◽

Cited By ~ 5

Author(s):

Vincenza Rita Lo Vasco

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Signal Transduction ◽

Membrane Trafficking ◽

Hormone Secretion ◽

Signal Transduction Pathway ◽

Brain Morphology ◽

Signal Transduction Pathways ◽

Transduction Pathway ◽

Cell Functions

Background: During aging and in age-associated disorders, such as Alzheimer's Disease (AD), learning abilities decline. Probably, disturbances in signal transduction in brain cells underlie the cognitive decline. The phosphorylation/dephosphorylation imbalance occurring in degenerating neurons was recently related to abnormal activity of one or more signal transduction pathways. AD is known to be associated with altered neuronal Ca2+ homeostasis, as Ca2+ accumulates in affected neurons leading to functional impairment. It is becoming more and more evident the involvement of signal transduction pathways acting upon Ca2+ metabolism and phosphorylation regulation of proteins. A growing interest raised around the role of signal transduction systems in a number of human diseases including neurodegenerative diseases, with special regard to the systems related to the phosphoinositide (PI) pathway and AD. The PI signal transduction pathway plays a crucial role, being involved in a variety of cell functions, such as hormone secretion, neurotransmitter signal transduction, cell growth, membrane trafficking, ion channel activity, cytoskeleton regulation, cell cycle control, apoptosis, cell and tissue polarity, and contributes to regulate the Ca2+ levels in the nervous tissue. Conclusion: A number of observations indicated that PI-specific phospholipase C (PLC) enzymes might be involved in the alteration of neurotransmission. To understand the role and the timing of action of the signalling pathways recruited during the brain morphology changes during the AD progression might help to elucidate the aetiopathogenesis of the disease, paving the way to prognosis refinement and/or novel molecular therapeutic strategies.

Download Full-text

Commonalities between Copper Neurotoxicity and Alzheimer’s Disease

Toxics ◽

10.3390/toxics9010004 ◽

2021 ◽

Vol 9 (1) ◽

pp. 4

Author(s):

Roshni Patel ◽

Michael Aschner

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Structural Changes ◽

Copper Ion ◽

Plaque Formation ◽

Ion Concentration ◽

Medical Community ◽

Disease Etiology ◽

Parent Protein ◽

Lead Zinc

Alzheimer’s disease, a highly prevalent form of dementia, targets neuron function beginning from the hippocampal region and expanding outwards. Alzheimer’s disease is caused by elevated levels of heavy metals, such as lead, zinc, and copper. Copper is found in many areas of daily life, raising a concern as to how this metal and Alzheimer’s disease are related. Previous studies have not identified the common pathways between excess copper and Alzheimer’s disease etiology. Our review corroborates that both copper and Alzheimer’s disease target the hippocampus, cerebral cortex, cerebellum, and brainstem, affecting motor skills and critical thinking. Additionally, Aβ plaque formation was analyzed beginning from synthesis at the APP parent protein site until Aβ plaque formation was completed. Structural changes were also noted. Further analysis revealed a relationship between amyloid-beta plaques and copper ion concentration. As copper ion levels increased, it bound to the Aβ monomer, expediting the plaque formation process, and furthering neurodegeneration. These conclusions can be utilized in the medical community to further research on the etiology of Alzheimer’s disease and its relationships to copper and other metal-induced neurotoxicity.

Download Full-text

Kinin B2 Receptor Activation Prevents the Evolution of Alzheimer’s Disease Pathological Characteristics in a Transgenic Mouse Model

Pharmaceuticals ◽

10.3390/ph13100288 ◽

2020 ◽

Vol 13 (10) ◽

pp. 288

Author(s):

Marielza Andrade Nunes ◽

Mariana Toricelli ◽

Natalia Mendes Schöwe ◽

Helena Nascimento Malerba ◽

Karis Ester Dong-Creste ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Death ◽

Functional Disability ◽

Therapeutic Option ◽

Receptor Activation ◽

Hippocampal Culture ◽

Kinin System ◽

Organotypic Hippocampal Culture ◽

Kallikrein Kinin System

Background: Alzheimer’s disease is mainly characterized by remarkable neurodegeneration in brain areas related to memory formation. This progressive neurodegeneration causes cognitive impairment, changes in behavior, functional disability, and even death. Our group has demonstrated changes in the kallikrein–kinin system (KKS) in Alzheimer’s disease (AD) experimental models, but there is a lack of evidence about the role of the KKS in Alzheimer’s disease. Aim: In order to answer this question, we evaluated the potential of the kinin B2 receptors (BKB2R) to modify AD characteristics, particularly memory impairment, neurodegeneration, and Aβ peptide deposition. Methods: To assess the effects of B2, we used transgenic Alzheimer’s disease mice treated with B2 receptor (B2R) agonists and antagonists, and performed behavioral and biochemical tests. In addition, we performed organotypic hippocampal culture of wild-type (WT) and transgenic (TG) animals, where the density of cytokines, neurotrophin BDNF, activated astrocyte marker S100B, and cell death were analyzed after treatments. Results: Treatment with the B2R agonist preserved the spatial memory of transgenic mice and decreased amyloid plaque deposition. In organotypic hippocampal culture, treatment with B2R agonist decreased cell death, neuroinflammation, and S100B levels, and increased BDNF release. Conclusions: Our results indicate that the kallikrein–kinin system plays a beneficial role in Alzheimer’s disease through B2R activation. The use of B2R agonists could, therefore, be a possible therapeutic option for patients diagnosed with Alzheimer’s disease.

Download Full-text

Microglia and its genetics in Alzheimer's Disease

Current Alzheimer Research ◽

10.2174/1567205018666211105140732 ◽

2021 ◽

Vol 18 ◽

Author(s):

Xinyan Liang ◽

Haijian Wu ◽

Mark Colt ◽

Xinying Guo ◽

Brock Pluimer ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Immune Cell ◽

Morphological Changes ◽

Association Studies ◽

Unmet Need ◽

Genome Wide Association Studies ◽

Protective Effects ◽

Risk Genes ◽

Main Component

: Alzheimer’s Disease (AD) is the most prevalent form of dementia across the world. While its discovery and pathological manifestations are centered on protein aggregations of amyloid-beta (Aβ) and hyperphosphorylated tau protein, neuroinflammation has emerged in the last decade as a main component of the disease in both pathogenesis and progression. As the main innate immune cell type in central nervous system (CNS), microglia play a very important role in regulating neuroinflammation, which occurs commonly in neurodegenerative conditions including AD. Under inflammatory response, microglia undergo morphological changes and status transition from homeostatic to activated forms. Different microglia subtypes displaying distinct genetic profiles have been identified in AD, and these signatures often link to AD risk genes identified from the genome-wide association studies (GWAS), such as APOE and TREM2. Furthermore, many of AD risk genes are highly enriched in microglia and specifically influence the functions of microglia in pathogenesis, e.g. releasing inflammatory cytokines and clearing Aβ. Therefore, building up a landscape of these risk genes in microglia, based on current preclinical studies and in the context of their pathogenic or protective effects, would largely help us to understand the complexed etiology of AD and provide new insight for the unmet need of effective treatment.

Download Full-text

Anti-Inflammatory Agents: An Approach to Prevent Cognitive Decline in Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-215125 ◽

2021 ◽

pp. 1-16

Author(s):

Staley A. Brod

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trial ◽

Cognitive Decline ◽

Immune Cell ◽

Inflammatory Responses ◽

Type I ◽

Type I Ifn ◽

Anti Inflammatory

Systemic inflammation is an organism’s response to an assault by the non-self. However, that inflammation may predispose humans to illnesses targeted to organs, including Alzheimer’s disease (AD). Lesions in AD have pro-inflammatory cytokines and activated microglial/monocyte/macrophage cells. Up to this point, clinical trials using anti-amyloid monoclonal antibodies have not shown success. Maybe it is time to look elsewhere by combating inflammation. Neuroinflammation with CNS cellular activation and excessive expression of immune cytokines is suspected as the “principal culprit” in the higher risk for sporadic AD. Microglia, the resident immune cell of the CNS, perivascular myeloid cells, and activated macrophages produce IL-1, IL-6 at higher levels in patients with AD. Anti-inflammatory measures that target cellular/cytokine-mediated damage provide a rational therapeutic strategy. We propose a clinical trial using oral type 1 IFNs to act as such an agent; one that decreases IL-1 and IL-6 secretion by activating lamina propria lymphocytes in the gut associated lymphoid tissue with subsequent migration to the brain undergoing inflammatory responses. A clinical trial would be double-blind, parallel 1-year clinical trial randomized 1 : 1 oral active type 1 IFN versus best medical therapy to determine whether ingested type I IFN would decrease the rate of cognitive decline in mild cognitive impairment or mild AD. Using cognitive psychometrics, imaging, and fluid biomarkers (MxA for effective type I IFN activity beyond the gut), we can determine if oral type I IFN can prevent cognitive decline in AD.

Download Full-text

Theracurmin supplementation may be a therapeutic option for older patients with alzheimer’s disease: a 6-month retrospective follow-up study

Current Alzheimer Research ◽

10.2174/1567205019666211221125255 ◽

2021 ◽

Vol 19 ◽

Author(s):

Fatma Sena Dost ◽

Derya Kaya ◽

Mehmet Selman Ontan ◽

Neziha Erken ◽

Esra Ateş Bulut ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Elderly Patients ◽

Therapeutic Option ◽

Disease Course ◽

Clock Drawing Test ◽

Global Challenge ◽

Follow Up Study ◽

Therapeutic Opportunity

Background: Alzheimer’s Disease (AD) is still a great global challenge and agents with various mechanisms represent a promising therapeutic opportunity. Theracurmin, a very highly absorbable curcumin formulation, was shown to improve memory and attention in non-demented people. Objective: To investigate the effect of Theracurmin on disease course in elderly patients with mild cognitive impairment (MCI) and AD. Methods: This follow-up study was performed retrospectively on 93 patients with MCI or AD. All patients underwent comprehensive geriatric assessment, including Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MOCA), clock-drawing test, activities of daily living (ADL), at baseline and end of the 6th-month. 19 patients with AD and 17 with MCI were treated with Theracurmin 180 mg/day per oral. Results: MMSE, MOCA and instrumental ADL scores decreased in AD patients that were not treated with Theracurmin (p<0.001, p=0.011, and p=0.004, respectively), whereas these scores remained stable in those treated with Theracurmin. This stabilization in the instrumental ADL was also observed in MCI patients treated with Theracurmin. During the follow-up, three of MCI patients who did not receive Theracurmin progressed to AD, whereas only one patient progressed in those who received it. Conclusion: Theracurmin seems to be a therapeutic option for elderly patients with AD and MCI via providing stabilization of the disease course by preventing progressive loss in cognitive functions and ADLs.

Download Full-text

Diagnosing Alzheimer’s Disease from Circulating Blood Leukocytes Using a Fluorescent Amyloid Probe

Journal of Alzheimer s Disease ◽

10.3233/jad-215402 ◽

2021 ◽

pp. 1-14

Author(s):

Stefanie A.G. Black ◽

Anastasiia A. Stepanchuk ◽

George W. Templeton ◽

Yda Hernandez ◽

Tomoko Ota ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protein Misfolding ◽

Mononuclear Cells ◽

Immune Cell ◽

Amyloid Β ◽

Csf Biomarkers ◽

Blood Leukocytes ◽

Peripheral Blood Mononuclear ◽

The Brain

Background: Toxic amyloid-β (Aβ) peptides aggregate into higher molecular weight assemblies and accumulate not only in the extracellular space, but also in the walls of blood vessels in the brain, increasing their permeability, and promoting immune cell migration and activation. Given the prominent role of the immune system, phagocytic blood cells may contact pathological brain materials. Objective: To develop a novel method for early Alzheimer’s disease (AD) detection, we used blood leukocytes, that could act as “sentinels” after trafficking through the brain microvasculature, to detect pathological amyloid by labelling with a conformationally-sensitive fluorescent amyloid probe and imaging with confocal spectral microscopy. Methods: Formalin-fixed peripheral blood mononuclear cells (PBMCs) from cognitively healthy control (HC) subjects, mild cognitive impairment (MCI) and AD patients were stained with the fluorescent amyloid probe K114, and imaged. Results were validated against cerebrospinal fluid (CSF) biomarkers and clinical diagnosis. Results: K114-labeled leukocytes exhibited distinctive fluorescent spectral signatures in MCI/AD subjects. Comparing subjects with single CSF biomarker-positive AD/MCI to negative controls, our technique yielded modest AUCs, which improved to the 0.90 range when only MCI subjects were included in order to measure performance in an early disease state. Combining CSF Aβ 42 and t-Tau metrics further improved the AUC to 0.93. Conclusion: Our method holds promise for sensitive detection of AD-related protein misfolding in circulating leukocytes, particularly in the early stages of disease.

Download Full-text

Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model

Gut ◽

10.1136/gutjnl-2018-317431 ◽

2019 ◽

Vol 69 (2) ◽

pp. 283-294 ◽

Cited By ~ 32

Author(s):

Min-Soo Kim ◽

Yoonhee Kim ◽

Hyunjung Choi ◽

Woojin Kim ◽

Sumyung Park ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gut Microbiota ◽

Neurofibrillary Tangles ◽

Immune Cell ◽

Amyloid Β ◽

Memory Deficits ◽

Faecal Microbiota ◽

Inflammatory Monocytes ◽

The Impact

ObjectiveCerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer’s disease (AD). Despite a strong influence of the intestinal microbiota on AD, the causal relationship between the gut microbiota and AD pathophysiology is still elusive.DesignUsing a recently developed AD-like pathology with amyloid and neurofibrillary tangles (ADLPAPT) transgenic mouse model of AD, which shows amyloid plaques, neurofibrillary tangles and reactive gliosis in their brains along with memory deficits, we examined the impact of the gut microbiota on AD pathogenesis.ResultsComposition of the gut microbiota in ADLPAPT mice differed from that of healthy wild-type (WT) mice. Besides, ADLPAPT mice showed a loss of epithelial barrier integrity and chronic intestinal and systemic inflammation. Both frequent transfer and transplantation of the faecal microbiota from WT mice into ADLPAPT mice ameliorated the formation of amyloid β plaques and neurofibrillary tangles, glial reactivity and cognitive impairment. Additionally, the faecal microbiota transfer reversed abnormalities in the colonic expression of genes related to intestinal macrophage activity and the circulating blood inflammatory monocytes in the ADLPAPT recipient mice.ConclusionThese results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLPAPT mice, providing new insights into the relationship between the gut (colonic gene expression, gut permeability), blood (blood immune cell population) and brain (pathology) axis and AD (memory deficits). Thus, restoring gut microbial homeostasis may have beneficial effects on AD treatment.

Download Full-text