Long-term dynamics of aberrant neuronal activity in awake Alzheimer\u2019s disease transgenic mice

F. Sun,V. Korzhova,S. Tahirovic,S. Liebscher,J. Rudan Njavro,J. Herms,P. Marinković,P. M. Goltstein

doi:10.1038/s42003-021-02884-7

Abstract

Alzheimer’s disease (AD) is associated with aberrant neuronal activity, which is believed to critically determine disease symptoms. How these activity alterations emerge, how stable they are over time, and whether cellular activity dynamics are affected by the amyloid plaque pathology remains incompletely understood. We here repeatedly recorded the activity from identified neurons in cortex of awake APPPS1 transgenic mice over four weeks during the early phase of plaque deposition using in vivo two-photon calcium imaging. We found that aberrant activity during this stage largely persisted over the observation time. Novel highly active neurons slowly emerged from former intermediately active neurons. Furthermore, activity fluctuations were independent of plaque proximity, but aberrant activity was more likely to persist close to plaques. These results support the notion that neuronal network pathology observed in models of cerebral amyloidosis is the consequence of persistent single cell aberrant neuronal activity, a finding of potential diagnostic and therapeutic relevance for AD.

Highlights

Alzheimer’s disease (AD) is associated with aberrant neuronal activity, which is believed to critically determine disease symptoms
To address the question of whether aberrant activity levels exist during wakefulness and whether they represent a stable or transient trait of neurons, we monitored the activity of individual identified neurons in cortex of awake Amyloid Precursor Protein – Presenilin 1 (APPPS1) transgenic mice and their non-transgenic littermates over four weeks by means of in vivo two-photon calcium imaging
Our data show that (a) hyperactivity is present in awake AD transgenic mice, (b) these highly active neurons develop slowly from former intermediately active neurons, (c) that activity levels largely persist over the four weeks investigational period in the early phase of the disease in the APPPS1 mouse model, and (d) that activity fluctuations are independent of amyloid plaque proximity

Summary

Introduction

Alzheimer’s disease (AD) is associated with aberrant neuronal activity, which is believed to critically determine disease symptoms. 1234567890():,; Alzheimer’s disease (AD), the most common form of dementia, is histopathologically characterized by the accumulation of diverse assemblies of the amyloid–beta peptide (Aβ) within the CNS, which are accompanied by aberrant neuronal hyper- and hypoactivity[1,2], alterations in oscillatory activity and network hypersynchrony[2] These aberrant neuronal activity levels and network dysfunction were shown to be one of the very early events of a pathogenic cascade in AD and to determine the level of cognitive impairment in affected individuals[2,3,4]. Our data show that (a) hyperactivity is present in awake AD transgenic mice, (b) these highly active neurons develop slowly from former intermediately active neurons, (c) that activity levels largely persist over the four weeks investigational period in the early phase of the disease in the APPPS1 mouse model, and (d) that activity fluctuations are independent of amyloid plaque proximity

Methods

Results

Conclusion