Intrahippocampal injection of a lentiviral vector expressing neurogranin enhances cognitive function in 5XFAD mice

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.

Decreased nesting behavior, selective increases in locomotor activity in a novel environment, and paradoxically increased open arm exploration in Neurogranin knockout mice

“…Behavioral phenotypes of commonly used AD model mice such as decreased nesting behavior, 31,35–37 hyperactivity, 31,37–41 impaired sociability, 35 impaired working/reference memory, 31,35,38,39,42–45 and abnormal sensorimotor gating 46,47 overlap with those of Nrgn KO mice, which suggests the potential of Nrgn KO as a model of AD. Considering this, a decrease in NRGN in the brains of AD model mice 48 and AD patients 6,7 may potentially explain some of the phenotypes or symptoms, respectively. Taken together, the behavioral phenotypes of Nrgn KO mice indicate that Nrgn KO mice might be a valuable animal model for further investigation of the pathophysiology and pathogenesis of neuropsychiatric disorders, including schizophrenia, ADHD, and AD.…”

Neurogranin: A Potential Biomarker of Neurological and Mental Diseases

“…Aging is associated with the cognitive decline as well as the decreased Ng levels in pyramidal neurons ( Mons et al, 2001 ). Ng reduction and cognitive deficit detected in 5XFAD mice are restored after the intra-hippocampal injection with an Ng-expressing lentiviral vector ( Jeon et al, 2018 ). On the basis of these basic studies, a series of researches published in the past decade focused on the associations between Ng and these kinds of diseases, which include, but are not limited to, AD, PD, CJD, HIV, infection (neuro-HIV), NS, TBI, AIS, and schizophrenia.…”

Ginsenoside Rg1 Prevents PTSD-Like Behaviors in Mice Through Promoting Synaptic Proteins, Reducing Kir4.1 and TNF-α in the Hippocampus

“…Experimental Protocol 3 Fourteen mice were habituated for 7 days and placed on stereotaxic instrument (RWD, Shenzhen, China) under isoflurane anesthesia. AAV2/5 GFAP-EGFP-shRNA Kir4.1 or AAV2/5 EGFP-shRNA control were bilaterally injected into the hippocampus (− 2.0mm anterior-posterior, 1.3-mm medial-lateral, and − 1.9-mm dorsal-ventral relative to the bregma) with 10-μL Hamilton syringe at a rate of 0.2 μL/min (2 μL on each side) (N = 7 in each group) [25]. After injection, the needles were retained for 5 min to allow the drug to be fully absorbed.…”