Marco Kramer ¹ Thu-Huong Hoang ¹ Honghong Yang ¹ Olena Shchyglo ¹ Juliane Böge ¹ Ute Neubacher ¹ Jens Colitti-Klausnitzer ¹ Denise Manahan-Vaughan ^2*

• ¹ Department of Neurophysiology, Faculty of Medicine, Ruhr University Bochum, Bochum, North Rhine-Westphalia, Germany
• ² Medical Faculty, Department of Neurophysiology, Ruhr University Bochum, Bochum, Germany

One of the puzzling aspects of sporadic Alzheimer's disease (AD) is how it commences. Changes in one key brain peptide, amyloid-beta (Ab), accompanies 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 Ab(1-42) is a key factor in early AD-pathogenesis. Furthermore, treatment of rodent brains with oligomeric Ab(1-42) either in vitro or in vivo, acutely impairs hippocampal synaptic plasticity, creating a link between Ab-pathology and learning impairments. Here, we show that a onceoff inoculation of the brains of healthy adult rats with oligomeric Ab(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 Ab homeostasis may suffice to trigger an irreversible cascade, underlying progressive loss of hippocampal function, that parallels the early stages of AD.