Intracellular signaling alterations are associated with Aβ aggregation and early memory deficits in an Alzheimer disease mouse model

FELD M; BLAKE MG; KRAWCZYK M; BARATTI CM; ROMANO A; BOCCIA MM

New Orleans

Encuentro; 11th Annual MCCS meeting; 2012

Molecular and Cellular Cognition Society

Alzheimer Disease (AD) is clinically featured by cognitive impairment and progressive memory loss, reaching severe cognitive decline in advanced stages. Senile plaques containing mainly amyloid-β peptides (Aβ), neurofibrillary tangles composed of hyperphosphorylated tau and neuronal loss are its major histological hallmarks. However, Aβ are elevated without plaque formation or nerve cell loss, yet learning and memory deficits are evident in early stages of AD. Transgenic mouse models of AD, such as the triple transgenic mice (3xTg) that progressively develop both amyloid and tangle neuropathology, are useful for elucidating factors that might affect the cognitive phenotype from incipient AD. Here we characterize the onset of learning and memory deficits at the age of 5 months in 3xTg mice, by using a Novel Object Recognition task (NOR). Concomitantly, we studied Aβ aggregation level as well as different molecular pathways in hippocampus (HIP) and prefrontal cortex (PFC) in order to establish potential early markers that likely correlate with the memory impairment observed. We observed a differential Aβ aggregation pattern for 3xTg mice depending on age and brain area. On the other hand, we found elevated ERK1/2 activity in PFC from 3xTg mice both extra-nuclear at 3 months and nuclear at 6 months of age. Taken together, our results suggest that the memory deficit found in 3xTg mice might be dependent on βA accumulation and aggregation, at least in PFC. It seems plausible that, as a consequence, ERK/MAPK pathway is early deregulated in this area and would be partially responsible for the mild cognitive impairment observed in early stages of AD.