Akt activation ameliorates deficits in hippocampal-dependent memory and activity-dependent synaptic protein synthesis in an Alzheimer's disease mouse model.

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, pGSK3ß, 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.

Sex difference in evolution of cognitive decline: studies on mouse model and the Dominantly Inherited Alzheimer Network cohort.

Women carry a higher burden of Alzheimer's disease (AD) compared to men, which is not accounted entirely by differences in lifespan. To identify the mechanisms underlying this effect, we investigated sex-specific differences in the progression of familial AD in humans and in APPswe/PS1ΔE9 mice. Activity dependent protein translation and associative learning and memory deficits were examined in APPswe/PS1ΔE9 mice and wild-type mice. As a human comparator group, progression of cognitive dysfunction was assessed in mutation carriers and non-carriers from DIAN (Dominantly Inherited Alzheimer Network) cohort. Female APPswe/PS1ΔE9 mice did not show recall deficits after contextual fear conditioning until 8 months of age. Further, activity dependent protein translation and Akt1-mTOR signaling at the synapse were impaired in male but not in female mice until 8 months of age. Ovariectomized APPswe/PS1ΔE9 mice displayed recall deficits at 4 months of age and these were sustained until 8 months of age. Moreover, activity dependent protein translation was also impaired in 4 months old ovariectomized APPswe/PS1ΔE9 mice compared with sham female APPswe/PS1ΔE9 mice. Progression of memory impairment differed between men and women in the DIAN cohort as analyzed using linear mixed effects model, wherein men showed steeper cognitive decline irrespective of the age of entry in the study, while women showed significantly greater performance and slower decline in immediate recall (LOGIMEM) and delayed recall (MEMUNITS) than men. However, when the performance of men and women in several cognitive tasks (such as Wechsler's logical memory) are compared with the estimated year from expected symptom onset (EYO) we found no significant differences between men and women. We conclude that in familial AD patients and mouse models, females are protected, and the onset of disease is delayed as long as estrogen levels are intact.

Endothelin-1 mediated vasoconstriction leads to memory impairment and synaptic dysfunction.

Cerebrovascular lesions seen as white matter hyperintensity in MRI of elderly population caused due to micro-infracts and micro-bleeds contributes to vascular dementia. Such vascular insult caused by impairment in blood flow to specific area in brain involving small vessels can gradually worsen the pathology leading to cognitive deficits. In the present study we developed a transient model of vaso-constriction to study the impact of such pathology by bilateral injection of ET-1 (Endothelin-1; a 21 amino acid vasoconstricting peptide) into lateral ventricles of C57 mice. The impediment in cerebral blood flow decreased CD31 expression in endothelial cells lining the blood vessels around the hippocampal region, leading to memory deficits after 7 days. Activity dependent protein translation, critical for synaptic plasticity was absent in synaptoneurosomes prepared from hippocampal tissue. Further, Akt1- mTOR signaling cascade was downregulated indicating the possible cause for loss of activity dependent protein translation. However, these effects were reversed after 30 days indicating the ephemeral nature of deficits following a single vascular insult. Present study demonstrates that vasoconstriction leading to memory deficit and decline in activity dependent protein translation in hippocampus as a potential molecular mechanism impacting synaptic plasticity.

Isoform-specific hyperactivation of calpain-2 occurs presymptomatically at the synapse in Alzheimer's disease mice and correlates with memory deficits in human subjects.

Calpain hyperactivation is implicated in late-stages of neurodegenerative diseases including Alzheimer's disease (AD). However, calpains are also critical for synaptic function and plasticity, and hence memory formation and learning. Since synaptic deficits appear early in AD pathogenesis prior to appearance of overt disease symptoms, we examined if localized dysregulation of calpain-1 and/or 2 contributes to early synaptic dysfunction in AD. Increased activity of synaptosomal calpain-2, but not calpain-1 was observed in presymptomatic 1 month old APPswe/PS1ΔE9 mice (a mouse model of AD) which have no evident pathological or behavioural hallmarks of AD and persisted up to 10 months of age. However, total cellular levels of calpain-2 remained unaffected. Moreover, synaptosomal calpain-2 was hyperactivated in frontal neocortical tissue samples of post-mortem brains of AD-dementia subjects and correlated significantly with decline in tests for cognitive and memory functions, and increase in levels of ß-amyloid deposits in brain. We conclude that isoform-specific hyperactivation of calpain-2, but not calpain-1 occurs at the synapse early in the pathogenesis of AD potentially contributing to the deregulation of synaptic signaling in AD. Our findings would be important in paving the way for potential therapeutic strategies for amelioration of cognitive deficits observed in ageing-related dementia disorders like AD.

Reactive Oxygen Species-Mediated Loss of Synaptic Akt1 Signaling Leads to Deficient Activity-Dependent Protein Translation Early in Alzheimer's Disease.

AIMS: Synaptic deficits are known to underlie the cognitive dysfunction seen in Alzheimer's disease (AD). Generation of reactive oxygen species (ROS) by ß-amyloid has also been implicated in AD pathogenesis. However, it is unclear whether ROS contributes to synaptic dysfunction seen in AD pathogenesis and, therefore, we examined whether altered redox signaling could contribute to synaptic deficits in AD. RESULTS: Activity dependent but not basal translation was impaired in synaptoneurosomes from 1-month old presymptomatic APPSwe/PS1ΔE9 (APP/PS1) mice, and this deficit was sustained till middle age (MA, 9-10 months). ROS generation leads to oxidative modification of Akt1 in the synapse and consequent reduction in Akt1-mechanistic target of rapamycin (mTOR) signaling, leading to deficiency in activity-dependent protein translation. Moreover, we found a similar loss of activity-dependent protein translation in synaptoneurosomes from postmortem AD brains. INNOVATION: Loss of activity-dependent protein translation occurs presymptomatically early in the pathogenesis of AD. This is caused by ROS-mediated loss of pAkt1, leading to reduced synaptic Akt1-mTOR signaling and is rescued by overexpression of Akt1. ROS-mediated damage is restricted to the synaptosomes, indicating selectivity. CONCLUSIONS: We demonstrate that ROS-mediated oxidative modification of Akt1 contributes to synaptic dysfunction in AD, seen as loss of activity-dependent protein translation that is essential for synaptic plasticity and maintenance. Therapeutic strategies promoting Akt1-mTOR signaling at synapses may provide novel target(s) for disease-modifying therapy in AD. Antioxid. Redox Signal. 27, 1269-1280.