AUTHOR=Kramer Marco , Hoang Thu-Huong , Yang Honghong , Shchyglo Olena , Böge Juliane , Neubacher Ute , Colitti-Klausnitzer Jens , Manahan-Vaughan Denise TITLE=Intracerebral inoculation of healthy non-transgenic rats with a single aliquot of oligomeric amyloid-β (1–42) profoundly and progressively alters brain function throughout life JOURNAL=Frontiers in Aging Neuroscience VOLUME=16 YEAR=2024 URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2024.1397901 DOI=10.3389/fnagi.2024.1397901 ISSN=1663-4365 ABSTRACT=

One of the puzzling aspects of sporadic Alzheimer’s disease (AD) is how it commences. Changes in one key brain peptide, amyloid-beta (Aβ), accompany disease progression, but whether this comprises a trigger or a consequence of AD is still a topic of debate. It is clear however that the cerebral presence of oligomeric Aβ (1–42) is a key factor in early AD-pathogenesis. Furthermore, treatment of rodent brains with oligomeric Aβ (1–42) either in vitro or in vivo, acutely impairs hippocampal synaptic plasticity, creating a link between Aβ-pathology and learning impairments. Here, we show that a once-off inoculation of the brains of healthy adult rats with oligomeric Aβ (1–42) exerts debilitating effects on the long-term viability of the hippocampus, one of the primary targets of AD. Changes are progressive: months after treatment, synaptic plasticity, neuronal firing and spatial learning are impaired and expression of plasticity-related proteins are changed, in the absence of amyloid plaques. Early changes relate to activation of microglia, whereas later changes are associated with a reconstruction of astroglial morphology. These data suggest that a disruption of Aβ homeostasis may suffice to trigger an irreversible cascade, underlying progressive loss of hippocampal function, that parallels the early stages of AD.