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The postulated central pathophysiological role of fibrillary A\u03b2 plaques has, however, been questioned, and small, soluble, pre-fibrillar A\u03b2 aggregates (oligomers) have been implicated as the crucial neurotoxic species in AD etiology. While the relationship between insoluble amyloid plaques and soluble A\u03b2 oligomers remains unclear, it has been hypothesized that plaques may serve as reservoirs, sequestering toxic A\u03b2 oligomers in the initial stages of the disease. Next to the canonical \u201cfull-length\u201d A\u03b21-40 and A\u03b21-42 peptides, a variety of N-terminally truncated A\u03b2 variants are present in AD brain tissue, with A\u03b24-42 peptides showing high abundance. The detrimental effects of these N-terminally truncated peptides have been previously studied using the Tg4-42\n                    <jats:sup>hom<\/jats:sup>\n                    mouse line, which displays neuron loss and cognitive deficits and accumulates A\u03b24-42 peptides in the CA1 region of the hippocampus albeit without amyloid plaque formation. This study aimed to investigate the relationship between soluble A\u03b24-42 peptides and insoluble extracellular A\u03b2 deposits by crossing the Tg4-42\n                    <jats:sup>hom<\/jats:sup>\n                    line with the plaque-bearing 5XFAD mouse model. We found that extracellular amyloid deposits in the hippocampus did not aggravate spatial memory deficits in Tg4-42\n                    <jats:sup>hom<\/jats:sup>\n                    mice but rescued recognition memory deficits. Moreover, while proximal CA1 pyramidal neuron loss in the hippocampus of Tg4-42\n                    <jats:sup>hom<\/jats:sup>\n                    mice was not affected by crossing with the 5XFAD line, a reduced loss of distal pyramidal neurons was observed in the filial line. Biochemically, 5XFAD\/Tg4-42\n                    <jats:sup>hom<\/jats:sup>\n                    mice showed a trend towards increased levels of insoluble A\u03b24-x peptides in the hippocampus. Taken together, these findings support the importance of soluble A\u03b2 oligomers in the pathogenesis of AD and provide evidence for the hypothesis that amyloid plaques provide buffering capacity.\n                  <\/jats:p>","DOI":"10.1007\/s12035-026-05912-x","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T17:33:58Z","timestamp":1778866438000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Amyloid Plaques Ameliorate Memory Deficits and Hippocampal Neuron Loss in an A\u03b24-42-Driven Alzheimer\u2019s Disease Mouse Model"],"prefix":"10.1007","volume":"63","author":[{"given":"Silvia","family":"Zampar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Merle","family":"Fricke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florian","family":"Kremser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan","family":"Talucci","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans Michael","family":"Maric","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans-Wolfgang","family":"Klafki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agueda","family":"Rostagno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olaf","family":"Jahn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sascha","family":"Weggen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge","family":"Ghiso","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oliver","family":"Wirths","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"issue":"12","key":"5912_CR1","doi-asserted-by":"publisher","first-page":"1168","DOI":"10.1097\/00005072-199812000-00009","volume":"57","author":"CM Hulette","year":"1998","unstructured":"Hulette CM, Welsh-Bohmer KA, Murray MG, Saunders AM, Mash DC, McIntyre LM (1998) Neuropathological and neuropsychological changes in \u201cnormal\u201d aging: evidence for preclinical Alzheimer disease in cognitively normal individuals. 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