{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"Research Square"}],"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T16:10:36Z","timestamp":1782835836515,"version":"3.54.5"},"posted":{"date-parts":[[2024,10,30]]},"group-title":"In Review","reference-count":88,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T00:00:00Z","timestamp":1730246400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,10,24]]},"abstract":"<title>Abstract<\/title>\n        <p>Norepinephrine (NE) modulates cognitive function, arousal, attention, and responses to novelty and stress, and also regulates neuroinflammation. We previously demonstrated behavioral and immunomodulatory effects of beta-adrenergic pharmacology in mouse models of Alzheimer's disease (AD). The current studies were designed to block noradrenergic signaling in 5XFAD mice through 1<bold>)<\/bold> chemogenetic inhibition of the locus coeruleus (LC), <bold>2)<\/bold>pharmacologic blocking of \u03b2-adrenergic receptors, and <bold>3) <\/bold>conditional deletion of \u03b21- or \u03b22-adrenergic receptors (adrb1 or adrb2) in microglia.\nFirst, brain-wide AD pathology was mapped in 3D by imaging immunolabeled, cleared 5XFAD brains to assess the overlap between A\u03b2 pathology, reactive microglia, and the loss of tyrosine hydroxylase (TH) expression in the catecholaminergic system. To examine the effects of inhibiting the LC NE system in the 5XFAD model, inhibitory (Gi) DREADD receptors were expressed specifically in LC NE neurons. LC NE neurons were chronically inhibited through the subcutaneous pump administration of the DREADD agonist clozapine-N-oxide (CNO). Plasma and brains were collected for assessment of neuroinflammation and pathology. A separate cohort of 5XFAD mice was chronically dosed with the beta-adrenergic antagonist propranolol or vehicle and evaluated for behavior, as well as post-mortem neuroinflammation and pathology. Finally, we used 5XFAD mice with conditional deletion of either adrb1 or adrb2 in microglia to assess neuroinflammation and pathology mediated by \u03b2-adrenergic signaling.\nUsing iDISCO, light sheet fluorescence microscopy, and novel analyses, we detected widespread microgliosis and amyloid pathology, along with modest TH downregulation in fibers across multiple brain regions, in contrast to the spatially limited TH downregulation observed in neurons. Both chemogenetic inhibition of LC adrenergic signaling and pharmacological inhibition of beta-adrenergic receptors potentiated neuroinflammation without altering amyloid beta pathology. Conditional deletion of adrb1 in microglia did not affect neuroinflammation. Conditional deletion of adrb2 in microglia attenuated inflammation and pathology in females but had no effect in males. Overall, these data support previous observations demonstrating the immunomodulatory effects of beta-adrenergic signaling in the pathophysiology of brain disorders and suggest that adrenergic receptors on cell types other than microglia, such as astrocytes, may predominantly mediate the disease-modifying effects of \u03b2-adrenergic agonists in the brain.<\/p>","DOI":"10.21203\/rs.3.rs-5328229\/v1","type":"posted-content","created":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T15:28:03Z","timestamp":1730302083000},"source":"Crossref","is-referenced-by-count":1,"title":["Impact of noradrenergic inhibition on neuroinflammation and pathophysiology in mouse models of Alzheimer's disease."],"prefix":"10.21203","author":[{"given":"Andrew K.","family":"Evans","sequence":"first","affiliation":[{"name":"Stanford University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heui Hye","family":"Park","sequence":"additional","affiliation":[{"name":"Stanford University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire E.","family":"Woods","sequence":"additional","affiliation":[{"name":"Stanford University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel K.","family":"Lam","sequence":"additional","affiliation":[{"name":"Stanford University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel Ryskamp","family":"Rijsketic","sequence":"additional","affiliation":[{"name":"Stanford University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Xu","sequence":"additional","affiliation":[{"name":"Stanford University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Chu","sequence":"additional","affiliation":[{"name":"Stanford University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Ciari","sequence":"additional","affiliation":[{"name":"Stanford University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Blumenfeld","sequence":"additional","affiliation":[{"name":"Stanford University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura M.","family":"Vidano","sequence":"additional","affiliation":[{"name":"Stanford University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nay L.","family":"Saw","sequence":"additional","affiliation":[{"name":"Stanford University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris D.","family":"Heifets","sequence":"additional","affiliation":[{"name":"Stanford University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehrdad","family":"Shamloo","sequence":"additional","affiliation":[{"name":"Stanford University"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","reference":[{"issue":"4","key":"ref1","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1002\/hipo.22394","article-title":"Neuromodulatory signaling in hippocampus-dependent memory retrieval","volume":"25","author":"Thomas SA","year":"2015","unstructured":"Thomas SA. 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