{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T17:15:36Z","timestamp":1779297336317,"version":"3.51.4"},"reference-count":169,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,5]],"date-time":"2021-08-05T00:00:00Z","timestamp":1628121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>This article prosecutes a case against the zoonotic pathogen <jats:italic>Mycobacterium avium<\/jats:italic> ss. <jats:italic>paratuberculosis<\/jats:italic> (MAP) as a precipitant of Alzheimer\u2019s disease (AD). Like the other major neurodegenerative diseases AD is, at its core, a proteinopathy. Aggregated extracellular amyloid protein plaques and intracellular tau protein tangles are the recognized protein pathologies of AD. Autophagy is the cellular housekeeping process that manages protein quality control and recycling, cellular metabolism, and pathogen elimination. Impaired autophagy and cerebral insulin resistance are invariant features of AD. With a backdrop of age-related low-grade inflammation (inflammaging) and heightened immune risk (immunosenescence), infection with MAP subverts glucose metabolism and further exhausts an already exhausted autophagic capacity. Increasingly, a variety of agents have been found to favorably impact AD; they are agents that promote autophagy and reduce insulin resistance. The potpourri of these therapeutic agents: mTOR inhibitors, SIRT1 activators and vaccines are seemingly random until one recognizes that all these agents also suppress intracellular mycobacterial infection. The zoonotic mycobacterial MAP causes a common fatal enteritis in ruminant animals. Humans are exposed to MAP from contaminated food products and from the environment. The enteritis in animals is called paratuberculosis or Johne\u2019s disease; in humans, it is the putative cause of Crohn\u2019s disease. Beyond Crohn\u2019s, MAP is associated with an increasing number of inflammatory and autoimmune diseases: sarcoidosis, Blau syndrome, autoimmune diabetes, autoimmune thyroiditis, multiple sclerosis, and rheumatoid arthritis. Moreover, MAP has been associated with Parkinson\u2019s disease. India is one county that has extensively studied the human bio-load of MAP; 30% of more than 28,000 tested individuals were found to harbor, or to have harbored, MAP. This article asserts an unfolding realization that MAP infection of humans 1) is widespread in its presence, 2) is wide-ranging in its zoonosis and 3) provides a plausible link connecting MAP to AD.<\/jats:p>","DOI":"10.3389\/fimmu.2021.714179","type":"journal-article","created":{"date-parts":[[2021,8,5]],"date-time":"2021-08-05T09:06:43Z","timestamp":1628154403000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Warm, Sweetened Milk at the Twilight of Immunity - Alzheimer\u2019s Disease - Inflammaging, Insulin Resistance, M. paratuberculosis and Immunosenescence"],"prefix":"10.3389","volume":"12","author":[{"given":"Coad Thomas","family":"Dow","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2018.109","article-title":"Promoting the Clearance of Neurotoxic Proteins in Neurodegenerative Disorders of Ageing","volume":"17","author":"Boland","year":"2018","journal-title":"Nat Rev Drug Discov"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.01.022","article-title":"Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities","volume":"93","author":"Menzies","year":"2017","journal-title":"Neuron"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1774","DOI":"10.1126\/science.1197623","article-title":"Decreased Clearance of CNS Beta-Amyloid in Alzheimer\u2019s Disease","volume":"330","author":"Mawuenyega","year":"2010","journal-title":"Science"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.12538","article-title":"Diversity of Astroglial Responses Across Human Neurodegenerative Disorders and Brain Aging","volume":"27","author":"Ferrer","year":"2017","journal-title":"Brain Pathol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2013.00054","article-title":"Autophagic Clearance of Bacterial Pathogens: Molecular Recognition of Intracellular Microorganisms","volume":"3","author":"Pareja","year":"2013","journal-title":"Front Cell Infect Microbiol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01483","article-title":"Macrophage Autophagy and Bacterial Infections","volume":"8","author":"Bah","year":"2017","journal-title":"Front Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.07.017","article-title":"Autophagy and Cellular Immune Responses","volume":"39","author":"Ma","year":"2013","journal-title":"Immunity"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz244","article-title":"Time to Test Antibacterial Therapy in Alzheimer\u2019s Disease","volume":"142","author":"Panza","year":"2019","journal-title":"Brain"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-141170","article-title":"The Microbiome and Disease: Reviewing the Links Between the Oral Microbiome, Aging, and Alzheimer\u2019s Disease","volume":"43","author":"Shoemark","year":"2015","journal-title":"J Alzheimers Dis"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2018.00159","article-title":"Infection of Fungi and Bacteria in Brain Tissue From Elderly Persons and Patients With Alzheimer\u2019s Disease","volume":"10","author":"Alonso","year":"2018","journal-title":"Front Aging Neurosci"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2018.00362","article-title":"Role of Microbes in the Development of Alzheimer\u2019s Disease: State of the Art - An International Symposium Presented at the 2017 IAGG Congress in San Francisco","volume":"9","author":"F\u00fcl\u00f6p","year":"2018","journal-title":"Front Genet"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1111\/ene.12477","article-title":"A Study on the Association Between Infectious Burden and Alzheimer\u2019s Disease","volume":"22","author":"Bu","year":"2015","journal-title":"Eur J Neurol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1212","DOI":"10.3390\/microorganisms8081212","article-title":"Systematic Assessment of Mycobacterium Avium Subspecies Paratuberculosis Infections From 1911-2019: A Growth Analysis of Association With Human Autoimmune Diseases","volume":"8","author":"Ekundayo","year":"2020","journal-title":"Microorganisms"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00096","article-title":"Mycobacterium Avium Ss. 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