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Abstract
Progressive cognitive declines are the main clinical symptoms of Alzheimer’s disease (AD). Cognitive impairment in AD is directly correlated with amyloid beta (Aβ)-mediated synaptic deficits. It is known that upregulation of neurogranin (Ng), a postsynaptic protein, contributes to the enhancement of synaptic plasticity and cognitive function. By contrast, downregulation of Ng expression results in learning and memory impairments. Interestingly, Ng expression is significantly reduced in the parenchyma of brains with AD. However, the pathological role that downregulated Ng plays in the cognitive dysfunctions observed in AD remains unclear. Therefore, the present study examined whether enhancing Ng expression affected cognitive functions in 5XFAD mice, an animal model of AD. We found that the Ng reductions and cognitive decline observed in 5XFAD mice were restored in mice that were intrahippocampally injected with an Ng-expressing lentiviral vector. Furthermore, overexpression of Ng upregulated expression of postsynaptic density protein-95 in the hippocampus of 5XFAD mice. These results suggest that the cause of cognitive decline in AD may be at least partially associated with reduced Ng levels, and thus, supplementation of Ng may be an appropriate therapeutic strategy for individuals with AD.
Highlights
Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders, and its main clinical symptoms are progressive cognition impairments
Synaptic failure has been directly linked to cognitive decline and dementia severity in AD,[3,4,5] suggesting that the memory loss of patients in the early stages of AD may be caused by synaptic dysfunction, rather than by neuronal death
Ability of the lentiviral vector to deliver Ng to the mouse brain In addition to the above in vitro test, we investigated gene expression mediated by the lentivirus-green fluorescent protein (GFP)-Ng in vivo
Summary
Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders, and its main clinical symptoms are progressive cognition impairments. AD is characterized by the accumulation of neurofibrillary tangles and amyloid plaques in the brain, resulting in the loss of neurons and synapses.[1] In the early stages of AD, the synaptic protein level is reduced by ~ 25%, indicating that synaptic loss is an early event in AD.[2] synaptic failure has been directly linked to cognitive decline and dementia severity in AD,[3,4,5] suggesting that the memory loss of patients in the early stages of AD may be caused by synaptic dysfunction, rather than by neuronal death. One factor that is known to cause synaptic dysfunction is amyloid beta (Aβ), which self-aggregates to form the amyloid plaques that are observed in AD.[5,6] In addition, Aβ contributes to suppression of basal synaptic transmission by facilitating endocytosis of N-methyl-D-aspartate glutamate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) from synapses.[7,8,9] Further, oligomers of Aβ decrease the number of dendritic spines and disrupt synaptic plasticity by shifting the balance between long-term potentiation (LTP) and long-term depression (LTD).[10]
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