Kommaddi, RP and Gowaikar, R and P A, H and Diwakar, L and Singh, K and Mondal, A (2024) Akt activation ameliorates deficits in hippocampal-dependent memory and activity-dependent synaptic protein synthesis in an Alzheimer's disease mouse model. In: Journal of Biological Chemistry, 300 (2).
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Abstract
Protein kinase-B (Akt) and the mechanistic target of rapamycin (mTOR) signaling pathways are implicated in Alzheimer's disease (AD) pathology. Akt/mTOR signaling pathways, activated by external inputs, enable new protein synthesis at the synapse and synaptic plasticity. The molecular mechanisms impeding new protein synthesis at the synapse in AD pathogenesis remain elusive. Here, we aimed to understand the molecular mechanisms prior to the manifestation of histopathological hallmarks by characterizing Akt1/mTOR signaling cascades and new protein synthesis in the hippocampus of WT and amyloid precursor protein/presenilin-1 (APP/PS1) male mice. Intriguingly, compared to those in WT mice, we found significant decreases in pAkt1, pGSK3β, pmTOR, pS6 ribosomal protein, and p4E-BP1 levels in both post nuclear supernatant and synaptosomes isolated from the hippocampus of one-month-old (presymptomatic) APP/PS1 mice. In synaptoneurosomes prepared from the hippocampus of presymptomatic APP/PS1 mice, activity-dependent protein synthesis at the synapse was impaired and this deficit was sustained in young adults. In hippocampal neurons from C57BL/6 mice, downregulation of Akt1 precluded synaptic activity�dependent protein synthesis at the dendrites but not in the soma. In three-month-old APP/PS1 mice, Akt activator (SC79) administration restored deficits in memory recall and activity-dependent synaptic protein synthesis. C57BL/6 mice administered with an Akt inhibitor (MK2206) resulted in memory recall deficits compared to those treated with vehicle. We conclude that dysregulation of Akt1/mTOR and its downstream signaling molecules in the hippocampus contribute to memory recall deficits and loss of activity-dependent synaptic protein synthesis. In AD mice, however, Akt activation ameliorates deficits in memory recall and activity-dependent synaptic protein synthesis. © 2024 The Authors
| Item Type: | Journal Article |
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| Publication: | Journal of Biological Chemistry |
| Publisher: | American Society for Biochemistry and Molecular Biology Inc. |
| Additional Information: | The copyright for this article belongs to author |
| Keywords: | Biosynthesis; Brain; Chemical activation; Mammals; Neurodegenerative diseases; Neurons; Signaling, Activity-dependent; Activity-dependent protein synthesis; Alzheimers disease; Amyloid precursor protein/presenilin-1; Amyloid precursor proteins; Dementia; Presenilins; Protein synthesis; Synaptic plasticity; Synaptosome, Proteins, 8 4 (1 aminocyclobutyl)phenyl 9 phenyl 1,2,4 triazolo3,4 f1,6naphthyridin 3(2h) one; amyloid precursor protein; glycogen synthase kinase 3beta; initiation factor 4E; mammalian target of rapamycin; presenilin 1; protein S6, adolescent; Akt/mTOR signaling; Alzheimer disease; animal experiment; animal model; animal tissue; Article; context-dependent memory; controlled study; down regulation; hippocampus; histopathology; male; molecular mechanics; mouse; nonhuman; protein synthesis; recall; supernatant; synaptosome |
| Department/Centre: | Division of Biological Sciences > Centre for Neuroscience Autonomous Societies / Centres > Centre for Brain Research |
| Date Deposited: | 04 Mar 2024 06:42 |
| Last Modified: | 04 Mar 2024 06:42 |
| URI: | https://eprints.iisc.ac.in/id/eprint/84159 |
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