Spatial learning and memory impairments are associated with increased neuronal activity in 5XFAD mouse as measured by manganese-enhanced magnetic resonance imaging

Xiang Tang,Xiao-Li Li,Xin-Yang Qi,Fang-Fang Wu,Li-Hua Gu,Zhi-Jun Zhang,Di Wu,Yan-Juan Wang,Lin Xu,Qing-Guo Ren,Xiao-Chun Chen,Bin-Bin Nie,Feng Bai

doi:10.18632/oncotarget.11353

Abstract

Dysfunction of neuronal activity is a major and early contributor to cognitive impairment in Alzheimer's disease (AD). To investigate neuronal activity alterations at early stage of AD, we encompassed behavioral testing and in vivo manganese-enhanced magnetic resonance imaging (MEMRI) in 5XFAD mice at early ages (1-, 2-, 3- and 5-month). The 5XFAD model over-express human amyloid precursor protein (APP) and presenilin 1 (PS1) harboring five familial AD mutations, which have a high APP expression correlating with a high burden and an accelerated accumulation of the 42 amino acid species of amyloid-β. In the Morris water maze, 5XFAD mice showed longer escape latency and poorer memory retention. In the MEMRI, 5XFAD mice showed increased signal intensity in the brain regions involved in spatial cognition, including the entorhinal cortex, the hippocampus, the retrosplenial cortex and the caudate putamen. Of note, the observed alterations in spatial cognition were associated with increased MEMRI signal intensity. These findings indicate that aberrant increased basal neuronal activity may contribute to the spatial cognitive function impairment at early stage of AD, and may further suggest the potential use of MEMRI to predict cognitive impairments. Early intervention that targets aberrant neuronal activity may be crucial to prevent cognitive impairment.

Highlights

Neuronal activity dysfunction is an important feature of Alzheimer’s disease (AD); such dysfunction typically progresses from early neuronal excitability/hyperactivity to later silencing/hypoactivity [1]
Did neuronal activity alterations emerge in the early ages of 5XFAD mice? Did neuronal activity alterations become more severe in 5XFAD mice with age? Did neuronal activity alterations associate with spatial cognitive function impairment in the early ages of 5XFAD mice? To test these hypothesis, the present study focused on the early stage by selecting four groups (1, 2, 3 and 5 months of age) of 5XFAD mice [26] compared with age-matched wild-type mice to investigate the following: 1) impairments in spatial learning and memory and their progression with age; 2) region-specific changes in basal neuronal activity in brain regions involved in spatial cognition by high-resolution manganeseenhanced magnetic resonance imaging (MEMRI); and 3) the correlation between spatial cognitive function and neuronal activity. (Figure 1)
The present study demonstrated that spatial cognitive function, especially memory function, is impaired in 5XFAD mice at early ages, and that spatial cognitive function in these animals is negatively correlated with abnormally increased neuronal activity in cognitive brain regions, including the retrosplenial cortex (RSC), the Hip, the Cpu and the entorhinal cortex (ERC)

Summary

Introduction

Neuronal activity dysfunction is an important feature of Alzheimer’s disease (AD); such dysfunction typically progresses from early neuronal excitability/hyperactivity to later silencing/hypoactivity [1]. The high-risk population of AD shows higher activity levels in multiple cognitive brain regions, including the frontal, entorhinal and posterior cingulate cortex (PCC) and the hippocampus, during working memory tasks compared with matched controls. This population includes apolipoprotein E ε4 carriers [5], non-demented carriers of a clusterin (CLU) allele [6] and carriers of the presymptomatic presenilin 1 gene (PS1) mutation [7]

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