{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T19:48:54Z","timestamp":1775072934412,"version":"3.50.1"},"reference-count":52,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T00:00:00Z","timestamp":1768780800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"DZNE Stiftung","award":["T0531\/43703\/2023\/hhe"],"award-info":[{"award-number":["T0531\/43703\/2023\/hhe"]}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["425899996"],"award-info":[{"award-number":["425899996"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>In both Alzheimer\u2019s disease (AD) patients and animal models, senile plaques are generally observed in the cerebral cortex rather than the cerebellum. The mechanisms underlying the regional resistance of the cerebellum to amyloid plaque deposition remain poorly understood. We investigated this cerebellar resistance using 5xFAD mice, an amyloidosis model with high expression of mutant human APP and PSEN1 in the cortex and cerebellum. In aged 5xFAD mice, the cerebellum had minimal amyloid-\u03b2 (A\u03b2) deposition despite robust transgene expression, correlating with lower expression levels of IBA1, CD68, TREM2, and CD36 (although elevated expression of CD45 and MHC I) compared to the cortex. Consistent with the absence of plaques, cerebellar tissue lacked the dystrophic VGLUT1-positive synaptic accumulations prominent in the cortex. Cerebellar microglia maintained a distinct, less inflammatory phenotype yet displayed efficient clearance activity. Notably, ASC inflammasome specks\u2014capable of seeding A\u03b2 aggregation\u2014were paradoxically more abundant in the cerebellum, implying that rapid A\u03b2 clearance prevents these seeds from driving plaque formation. Furthermore, key extracellular matrix (ECM) proteoglycans brevican and aggrecan were elevated in the 5xFAD cerebellum. Cerebellar microglia showed enhanced internalization of brevican alongside small A\u03b2 aggregates, exceeding that in cortical microglia. These findings indicate that region-specific microglial and ECM interactions\u2014particularly efficient uptake and degradation of ECM\u2013A\u03b2 co-aggregates\u2014may underlie the cerebellum\u2019s resilience to amyloid plaque pathology.<\/jats:p>","DOI":"10.3390\/cells15020182","type":"journal-article","created":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T14:58:54Z","timestamp":1768834734000},"page":"182","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cerebellar Resistance to Amyloid Plaque Deposition and Elevated Microglial ECM Proteoglycan Uptake in 5xFAD Mice"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3525-8445","authenticated-orcid":false,"given":"Carla","family":"Cangalaya","sequence":"first","affiliation":[{"name":"Molecular Neuroplasticity Research Group, German Center for Neurodegenerative Diseases (DZNE), Leipziger Str. 44, Haus 64, D-39120 Magdeburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henning Peter","family":"D\u00fcsedau","sequence":"additional","affiliation":[{"name":"Institute of Inflammation and Neurodegeneration, Health Campus Immunology, Infectiology and Inflammation (GC-I3), Otto-von-Guericke-University, D-39120 Magdeburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ildiko Rita","family":"Dunay","sequence":"additional","affiliation":[{"name":"Institute of Inflammation and Neurodegeneration, Health Campus Immunology, Infectiology and Inflammation (GC-I3), Otto-von-Guericke-University, D-39120 Magdeburg, Germany"},{"name":"Center for Behavioral Brain Sciences (CBBS), D-39106 Magdeburg, Germany"},{"name":"Center for Intervention and Research on Adaptive and Maladaptive Brain Circuits Underlying Mental Health (C-I-R-C), German Center for Mental Health (DZPG), Halle-Jena-Magdeburg, D-07743 Jena, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0472-0553","authenticated-orcid":false,"given":"Alexander","family":"Dityatev","sequence":"additional","affiliation":[{"name":"Molecular Neuroplasticity Research Group, German Center for Neurodegenerative Diseases (DZNE), Leipziger Str. 44, Haus 64, D-39120 Magdeburg, Germany"},{"name":"Center for Behavioral Brain Sciences (CBBS), D-39106 Magdeburg, Germany"},{"name":"Medical Faculty, Otto-von-Guericke-University, D-39120 Magdeburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2872-7709","authenticated-orcid":false,"given":"Stoyan","family":"Stoyanov","sequence":"additional","affiliation":[{"name":"Molecular Neuroplasticity Research Group, German Center for Neurodegenerative Diseases (DZNE), Leipziger Str. 44, Haus 64, D-39120 Magdeburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"595","DOI":"10.15252\/emmm.201606210","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease at 25 years","volume":"8","author":"Selkoe","year":"2016","journal-title":"EMBO Mol. 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