Acute Down-regulation of BDNF Signaling Does Not Replicate Exacerbated Amyloid-β Levels and Cognitive Impairment Induced by Cholinergic Basal Forebrain Lesion.

Marion T Turnbull,Elizabeth J Coulson,Zoran Boskovic

doi:10.3389/fnmol.2018.00051

Abstract

Degeneration of basal forebrain cholinergic neurons (BFCNs) precedes hippocampal degeneration and pathological amyloid-beta (Aβ) accumulation, and underpins the development of cognitive dysfunction in sporadic Alzheimer’s disease (AD). We hypothesized that degeneration of BFCNs causes a decrease in neurotrophin levels in innervated brain areas, which in turn promotes the development of Aβ pathology and cognitive impairment. Here we show that lesion of septo-hippocampal BFCNs in a pre-symptomatic transgenic amyloid AD mouse model (APP/PS1 mice) increases soluble Aβ levels in the hippocampus, and induces cognitive deficits in a spatial memory task that are not seen in either unlesioned APP/PS1 or non-transgenic littermate control mice. Furthermore, the BFCN lesion results in decreased levels of brain-derived neurotrophic factor (BDNF). However, viral knockdown of neuronal BDNF in the hippocampus of APP/PS1 mice (in the absence of BFCN loss) neither increased the level of Aβ nor caused cognitive deficits. These results suggest that the cognitive decline and Aβ pathology induced by BFCN loss occur independent of dysfunctional neuronal BDNF signaling, and may therefore be directly underpinned by reduced cholinergic neurotransmission.

Highlights

Alzheimer’s disease (AD) is histopathologically characterized by the accumulation of two proteins: extracellular deposits of amyloid-β (Aβ) that form amyloid plaques, and intracellular inclusions of the microtubule-associated protein tau that give rise to neurofibrillary tangles (NFTs)
We show that basal forebrain cholinergic neurons (BFCNs) lesions in adult mice induce reduced neurotrophin signaling, this loss of neuronal brainderived neurotrophic factor (BDNF) is unlikely to be directly responsible for the coincident increase in Aβ accumulation
We report that loss of cholinergic neurons in young presymptomatic Aβ-overproducing mice triggers an increase in the level of soluble Aβ42 in the hippocampus, a post-synaptic target of BFCNs, causing cognitive dysfunction in two hippocampal-dependent spatial navigation tasks

Summary

INTRODUCTION

Alzheimer’s disease (AD) is histopathologically characterized by the accumulation of two proteins: extracellular deposits of amyloid-β (Aβ) that form amyloid plaques, and intracellular inclusions of the microtubule-associated protein tau that give rise to neurofibrillary tangles (NFTs) In conjunction with this pathology, post-mortem assessment of the brains of AD patients has shown that selective degeneration of the cholinergic neurons in the basal forebrain is a significant pathological feature of the sporadic form of the disease and likely underpins aspects of cognitive decline (Mesulam, 2004; Contestabile, 2011; Schliebs and Arendt, 2011). An exacerbation in tau pathology is not seen following BFCN lesioning in tau-only transgenic mice (Turnbull and Coulson, 2017), indicating that this pathology is independent of cholinergic degeneration, and is likely driven by the induced Aβ accumulation It remains unclear how reduced cholinergic innervation results in an increase in Aβ in the cortex and/or hippocampus. In order to test the role of impaired cholinergic and neurotrophic signaling in the development of AD, we compared the effect of lesioning BFCNs with that of an acute reduction in BDNF expression in the hippocampus

MATERIALS AND METHODS

RESULTS

Findings

DISCUSSION