ROLE OF AKT-MTOR SIGNALING IN EARLY HIPPOCAMPAL DYSFUNCTION IN A TRANSGENIC MOUSE MODEL OF ALZHEIMER’S DISEASE
Alzheimer's & Dementia(2019)
Abstract
Memory loss, though not the only behavioral symptom associated with Alzheimer's disease (AD) is arguably the most debilitating. Sufficient evidence exists to suggest that dysfunction of the hippocampal-entorhinal circuitry leads to memory impairments in AD. Our objective was to investigate whether structural and functional deficits seen in the hippocampal area precede emergence of clinical symptoms. Male APPSwe/PS1ΔE9 (APP/PS1) mice were used throughout the study. Memory impairment of young AD mice was tested using contextual fear conditioning (cFc), Morris water maze, and object recognition tasks. Golgi staining was done on brains of 1-month-old APP/PS1 mice and then sections were cut to obtain CA1 region of hippocampus. Structural data on the type and number of spines was obtained using Neurolucida imaging system. To measure activity dependent translation at the synapse, radiolabeled methionine incorporation assay was performed with synapto-neurosomes. This was followed by immuno-blotting experiments to test for repression of Akt-mTOR signaling, which is involved in protein translation at the synapse. Pan Akt inhibitor and activator were injected intrathecally in mice followed by cFC protocol. We observed memory deficits specific to contextual memory in young AD mice. At the structural level we observed, loss in density of mushroom spines compared to other types of spines specifically in tertiary neurites. Protein translation assay revealed that synaptic protein translation was impaired in hippocampus in young AD mice. Further, levels of phosphorylated forms of proteins that are part of the Akt signaling cascade were reduced. However, treatment of AD mice with Akt activator led to reversal of memory deficits. We observed memory deficits specific to contextual memory in young AD mice. At the structural level we observed, loss in density of mushroom spines compared to other types of spines specifically in tertiary neurites. Protein translation assay revealed that synaptic protein translation was impaired in hippocampus in young AD mice. Further, levels of phosphorylated forms of proteins that are part of the Akt signaling cascade were reduced. However, treatment of AD mice with Akt activator led to reversal of memory deficits.
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Alzheimer's Disease
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