{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T12:42:56Z","timestamp":1793104976838,"version":"4.5.0"},"reference-count":120,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T00:00:00Z","timestamp":1686268800000},"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. Pharmacol."],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is the most common form of neurodegenerative disease and disability in the elderly; it is estimated to account for 60%\u201370% of all cases of dementia worldwide. The most relevant mechanistic hypothesis to explain AD symptoms is neurotoxicity induced by aggregated amyloid-\u03b2 peptide (A\u03b2) and misfolded tau protein. These molecular entities are seemingly insufficient to explain AD as a multifactorial disease characterized by synaptic dysfunction, cognitive decline, psychotic symptoms, chronic inflammatory environment within the central nervous system (CNS), activated microglial cells, and dysfunctional gut microbiota. The discovery that AD is a neuroinflammatory disease linked to innate immunity phenomena started in the early nineties by several authors, including the ICC\u00b4s group that described, in 2004, the role IL-6 in AD-type phosphorylation of tau protein in deregulating the cdk5\/p35 pathway. The \u201cTheory of Neuroimmunomodulation\u201d, published in 2008, proposed the onset and progression of degenerative diseases as a multi-component \u201cdamage signals\u201d phenomena, suggesting the feasibility of \u201cmultitarget\u201d therapies in AD. This theory explains in detail the cascade of molecular events stemming from microglial disorder through the overactivation of the Cdk5\/p35 pathway. All these knowledge have led to the rational search for inflammatory druggable targets against AD. The accumulated evidence on increased levels of inflammatory markers in the cerebrospinal fluid (CSF) of AD patients, along with reports describing CNS alterations caused by senescent immune cells in neuro-degenerative diseases, set out a conceptual framework in which the neuroinflammation hypothesis is being challenged from different angles towards developing new therapies against AD. The current evidence points to controversial findings in the search for therapeutic candidates to treat neuroinflammation in AD. In this article, we discuss a neuroimmune-modulatory perspective for pharmacological exploration of molecular targets against AD, as well as potential deleterious effects of modifying neuroinflammation in the brain parenchyma. We specifically focus on the role of B and T cells, immuno-senescence, the brain lymphatic system (BLS), gut-brain axis alterations, and dysfunctional interactions between neurons, microglia and astrocytes. We also outline a rational framework for identifying \u201cdruggable\u201d targets for multi-mechanistic small molecules with therapeutic potential against AD.<\/jats:p>","DOI":"10.3389\/fphar.2023.1161850","type":"journal-article","created":{"date-parts":[[2023,6,12]],"date-time":"2023-06-12T09:37:06Z","timestamp":1686562626000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":88,"title":["Revisiting the neuroinflammation hypothesis in Alzheimer\u2019s disease: a focus on the druggability of current targets"],"prefix":"10.3389","volume":"14","author":[{"given":"Maylin","family":"Wong-Guerra","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila","family":"Calfio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo B.","family":"Maccioni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonel E.","family":"Rojo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e29738","DOI":"10.7554\/eLife.29738","article-title":"Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI","volume":"6","author":"Absinta","year":"2017","journal-title":"Elife"},{"key":"B2","doi-asserted-by":"publisher","first-page":"252","DOI":"10.3389\/fnagi.2020.00252","article-title":"Mitochondrial dysfunction and Alzheimer's disease: Role of microglia","volume":"12","author":"Agrawal","year":"2020","journal-title":"Front. aging Neurosci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1176\/ajp.151.8.1105","article-title":"Inflammatory mechanisms in Alzheimer's disease: Implications for therapy","volume":"151","author":"Aisen","year":"1994","journal-title":"Am. 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