Early effects of Aβ1-42 oligomers injection in mice: Involvement of PI3K/Akt/GSK3 and MAPK/ERK1/2 pathways

• Aβ oligomers (AβO) injection induces learning and memory impairments.
• AβO injection increases oxidative stress and GSH levels.
• AβO injection induces caspase-9 activation.
• AβO injection decreases immunofluorescence reactivity of synaptophysin.
• AβO toxicity leads to the activation of Akt and ERK1/2, and decreases GSK3 activity.

Neuronal and synaptic loss are the best pathological correlates for memory decline in Alzheimer's disease (AD). Soluble beta-amyloid oligomers (AβO) are considered to putatively play a crucial role in the early synapse loss and cognitive impairment observed in AD. Evidence suggests that oxidative stress and apoptosis are involved in the mechanism of Aβ-induced neurotoxicity and AD pathogenesis. This study aimed to explore the molecular mechanisms that contribute to the early memory deficits induced by intracerebroventricular injection of AβO in mice. Ten days after a single AβO injection memory impairments were observed, as measured by Morris water maze and novel object recognition tests. Cognitive decline was associated with increased oxidative stress, caspase-9 activation, and decreased hippocampal synaptophysin immunoreactivity. Furthermore, GSH levels were significantly higher in AβO-injected mice than in sham mice, showing that a protective mechanism might develop due to oxidative stress. Additionally, AβO-induced toxicity was aligned with an increment of the activation of Akt and ERK1/2, and reduced activity of GSK3. These findings suggest that AβO injection triggers a cascade of events that mimic the key neuropathological hallmarks of AD. Aβ acute injection helps to better understand how this peptide impairs specific signaling pathways leading to synaptic and memory dysfunctions. Thus, this model is a valid tool for investigating AD and may suggest a new way to develop neuroprotective therapies at such early stages of the disease.