{"id":3961,"date":"2020-11-01T02:25:20","date_gmt":"2020-11-01T02:25:20","guid":{"rendered":"https:\/\/fohs.bgu.ac.il\/monsonegolab\/?p=3961"},"modified":"2021-03-16T09:20:43","modified_gmt":"2021-03-16T09:20:43","slug":"immune-mechanisms-in-alzheimers-disease","status":"publish","type":"post","link":"https:\/\/fohs.bgu.ac.il\/monsonegolab\/projects\/immune-mechanisms-in-alzheimers-disease\/","title":{"rendered":"Immune mechanisms in aging and neurodegenerative diseases."},"content":{"rendered":"

Alzheimer\u2019s disease (AD) is the most common form of dementia, with prevalence progressively increasing with aging. Pathological hallmarks of the disease include accumulation of amyloid-beta (A\u03b2) peptides and neurofibrillary tangles in the brain associated with glial activation and\u00a0<\/span>synpatotoxicity<\/span>. In addition, AD involves peripheral and brain-endogenous inflammatory processes that appear to enhance disease progression.<\/span>\u00a0<\/span><\/p>\n

Our ongoing studies, using animal models of Alzheimer\u2019s disease, unveil the inflammatory role of microglial subsets, particularly those holding a dialogue with peripheral leukocytes, in the disease process. <\/em><\/p>\n

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CD4 T cells form cytotoxic or beneficial effector functions within the CNS (Mittal et al., 2019; Eremenko et al., 2019)<\/p><\/div>\n

In addition, we study\u00a0<\/span>how the activation of astrocytes, being key modulators\u00a0<\/span>of<\/span>\u00a0the blood-brain-barrier and the neuronal network, impacts the disease process.\u00a0<\/span>\u00a0<\/span><\/p>\n

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Astrocyte activation in animal models of Alzheimer disease (Muraleedharan A., et al., 2020)<\/p><\/div>\n

Apart from activation of an innate immune response in the\u00a0<\/span>b<\/span>rain, m<\/span>ore than a decade ago a new therapeutic paradigm has emerged for AD, namely the activation of the adaptive immune system directly against the self-peptide A\u03b2, aiming at lowering its accumulation\u00a0<\/span>and neurotoxicity<\/span>. This was the first time that a brain peptide was used to vaccinate human subjects in a manner similar to classic viral or bacterial vaccines. The vaccination approach took several turns, from initially active to passive and then back to\u00a0<\/span>modified active vaccines. As the two first approaches to date failed to show sufficient efficacy, the latter is presently being evaluated in\u00a0<\/span>ongoing clinical trials.\u00a0<\/span>In the\u00a0<\/span>review<\/span>\u00a0<\/span>(<\/span><\/i>CD4 T cells in immunity and immunotherapy of Alzheimer’s disease.<\/span><\/i><\/a>\u00a0<\/span><\/i>Immunology<\/span><\/i><\/b>. 2013<\/span><\/i>)<\/span><\/i>,\u00a0<\/span>we\u00a0<\/span>summarize the immu<\/span>nogenic characteristics of A\u03b2 in human and mice and discuss past, present and future Ai<\/span>-based immunotherapeutic approaches for AD. We emphasize potential pathogenic and beneficial roles of CD4 T cells in light of the general decline in T-cell responsiveness evident in\u00a0<\/span>aging<\/span>.<\/span>\u00a0More recently<\/span>,<\/span>\u00a0the stu<\/span>dies<\/span>\u00a0by\u00a0<\/span>Fisher et al., 2014<\/span><\/i>,<\/span><\/i>\u00a0<\/span><\/i>Strominger<\/span><\/i>\u00a0et al., 2018<\/span><\/i>, Mittal et al., 2019 and Eremenko et al.,<\/span><\/i>\u00a0<\/span><\/i>2019<\/span><\/i>,\u00a0<\/span>provide<\/span>d<\/span>\u00a0mechanistic insight<\/span>s<\/span>\u00a0to the migration of CD4 T cells into the\u00a0<\/span>choroid plexus and into the\u00a0<\/span>brain parenchyma and highlight implications\u00a0<\/span>to<\/span> brain immunity and repair. <\/span>Current work is devoted to further understanding the dialogue between the immune system and the brain and to generate immunotherapeutic T cells as targeted drug-delivery vehicles.<\/em><\/p>\n

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The choroid plexus as a lymphoid-like structure
(Strominger et al., 2018)<\/p><\/div>\n

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Activated leukocytes (red) attack amyloid plaques in the brain of a mouse model of Alzheimer disease
(Strominger et al., 2018)<\/p><\/div>\n

 <\/p>\n

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Brain-Immune interactions at the choroid plexus: A semi-lymphoid structure that regulates brain inflammation
(Strominger et al., 2018; Mittal et al., 2019; Eremenko et al., 2019)<\/p><\/div>\n

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Immune biomarkers of aging and age-related diseases<\/u><\/p>\n

Among the many possible aging-related factors involved in the development of age-related diseases, senescence of the immune system may significantly enhance <\/span>inflammation and neuronal damage<\/span>\u00a0<\/span>in the brain and\u00a0<\/span>thus facilitate<\/span>\u00a0<\/span>cognitive<\/span>\u00a0decline. A direct consequence of\u00a0<\/span>immunosenescence<\/span>\u00a0is the increased frequency of systemic infections and, in fact, many who die with AD have previously suffered from a severe infection<\/span>\u00a0and\/or chronic inflammation<\/span>.\u00a0<\/span>\u00a0<\/span><\/p>\n

While chronic\u00a0<\/span>brain\u00a0<\/span>inflammation progresses throughout the disease, the specific arm of the immune system, i.e., brain-specific lymphocytes, may also be stimulated. In contrast to previous assumptions, our findings in\u00a0<\/span>people<\/span>\u00a0with AD demonstrate<\/span>d<\/span>\u00a0that a specific immune response to A<\/span>-beta<\/span>\u00a0<\/span>is indeed significantly induced in both elderly individuals and patients with AD as compared to middle-aged individuals<\/span>\u00a0(<\/span>Monsonego et al., 2003<\/span>)<\/span>. The nature and role of this immune response to\u00a0<\/span>A<\/span>-beta<\/span>\u00a0<\/span>is yet to be investigated, and may result in new diagnostic and immunotherapeutic approaches.\u00a0<\/span>More recently we have shown that aging results in the accumulation of effector CD4 T cells exhibiting extremely dysregulated functions\u00a0<\/span>(<\/span><\/i>Harpaz<\/span><\/i>\u00a0et al., 2017<\/span><\/i>).<\/span><\/i> Since these dysregulated T cells may significantly impact inflammatory processes in the brain of people with AD, in collaboration with Prof. Esti Yeger-Lotem and Prof. Nir Friedman we initiated a single-cell RNA analysis of leukocytes to reveal how aging impacts the landscape of lymphocytes as a key process that may underlie declined immunity and chronic inflammation in the elderly <\/span>(Elyahu et al., 2019; Elayhu et al., 2020).<\/em> Current research aims to further reveal the cellular and molecular characteristics of dysregulated CD4 T cells in aging and neurodegenerative processes both in human and in animal models.<\/em><\/p>\n

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CD4 T cells undergo extensive diversification with age
(Elayhu et al., 2019; 2020)<\/p><\/div>\n","protected":false},"excerpt":{"rendered":"

Alzheimer\u2019s disease (AD) is the most common form of dementia, with prevalence progressively increasing with aging. Pathological hallmarks of the disease include accumulation of amyloid-beta (A\u03b2) peptides and neurofibrillary tangles in the brain associated with glial activation and\u00a0synpatotoxicity. In addition, AD involves peripheral and brain-endogenous inflammatory processes that appear to enhance disease progression.\u00a0 Our ongoing […]<\/p>\n","protected":false},"author":1,"featured_media":4051,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[58],"tags":[65,64,66],"class_list":["post-3961","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-projects","tag-aging","tag-immune-mechanisms","tag-neurodegenerative-diseases"],"_links":{"self":[{"href":"https:\/\/fohs.bgu.ac.il\/monsonegolab\/wp-json\/wp\/v2\/posts\/3961","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/fohs.bgu.ac.il\/monsonegolab\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/fohs.bgu.ac.il\/monsonegolab\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/fohs.bgu.ac.il\/monsonegolab\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/fohs.bgu.ac.il\/monsonegolab\/wp-json\/wp\/v2\/comments?post=3961"}],"version-history":[{"count":10,"href":"https:\/\/fohs.bgu.ac.il\/monsonegolab\/wp-json\/wp\/v2\/posts\/3961\/revisions"}],"predecessor-version":[{"id":4248,"href":"https:\/\/fohs.bgu.ac.il\/monsonegolab\/wp-json\/wp\/v2\/posts\/3961\/revisions\/4248"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/fohs.bgu.ac.il\/monsonegolab\/wp-json\/wp\/v2\/media\/4051"}],"wp:attachment":[{"href":"https:\/\/fohs.bgu.ac.il\/monsonegolab\/wp-json\/wp\/v2\/media?parent=3961"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/fohs.bgu.ac.il\/monsonegolab\/wp-json\/wp\/v2\/categories?post=3961"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/fohs.bgu.ac.il\/monsonegolab\/wp-json\/wp\/v2\/tags?post=3961"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}