Brain-derived neurotrophic factor protects against tau-related neurodegeneration of Alzheimer’s disease

S-S Jiao,L-L Zhang,Y-H Liu,L-L Shen,Y-J Wang,H-D Zhou,X-L Bu,C Zhu,X-F Zhou,C-H Liu,J Tan,J Götz,X-Q Yao,D G Walker

doi:10.1038/tp.2016.186

Abstract

Reduced expression of brain-derived neurotrophic factor (BDNF) has a crucial role in the pathogenesis of Alzheimer's disease (AD), which is characterized with the formation of neuritic plaques consisting of amyloid-beta (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau protein. A growing body of evidence indicates a potential protective effect of BDNF against Aβ-induced neurotoxicity in AD mouse models. However, the direct therapeutic effect of BDNF supplement on tauopathy in AD remains to be established. Here, we found that the BDNF level was reduced in the serum and brain of AD patients and P301L transgenic mice (a mouse model of tauopathy). Intralateral ventricle injection of adeno-associated virus carrying the gene encoding human BDNF (AAV-BDNF) achieved stable expression of BDNF gene and restored the BDNF level in the brains of P301L mice. Restoration of the BDNF level attenuated behavioral deficits, prevented neuron loss, alleviated synaptic degeneration and reduced neuronal abnormality, but did not affect tau hyperphosphorylation level in the brains of P301L mice. Long-term expression of AAV-BDNF in the brain was well tolerated by the mice. These findings suggest that the gene delivery of BDNF is a promising treatment for tau-related neurodegeneration for AD and other neurodegenerative disorders with tauopathy.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia, causing a progressive decline of cognitive functions
Serum Brain-derived neurotrophic factor (BDNF) was significantly reduced in AD patients compared with age- and sex-matched HE controls (Figure 1a, source data of participants shown in Supplementary Table), and the detection rate of cerebrospinal fluid BDNF was lower in the AD group than in the HE group (Figure 1b)
From 4 months of age, P301L mice began to show BDNF reduction in both blood and brains compared with age- and sexmatched Wt littermate controls, and the extent of BDNF reduction became more obvious with aging (Figure 1f, g)

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia, causing a progressive decline of cognitive functions. It is suggested that the C270T (a nucleotide substitution in a noncoding region) and Val66Met (a missense mutation at the codon 66) polymorphisms of the BDNF gene confer susceptibility to AD,[7,8,9,10] and AD subjects show reduced mRNA and protein levels of BDNF in the serum and brain as compared with healthy elderly controls.[11,12,13,14] Importantly, higher expression of BDNF slows down cognitive decline in the elderly, especially in the setting of advancing AD neuropathology, indicating that the brain BDNF level could be used as a novel marker for evaluating AD progression.[14,15] it is conceivable to increase BDNF levels by directly supplementing BDNF or indirectly stimulating BDNF expression as a potential disease-modifying approach for AD.[16] Consistently, in vitro and in vivo experiments demonstrate that BDNF has neuroprotective effects against the cytotoxic effects and learning deficits induced by Aβ.[17,18] BDNF gene delivery in Aβ precursor protein (APP)-transgenic mice improves learning and memory, and reserves synapse and cell loss caused by APP mutation.[19,20] In general, these lines of evidence suggest that direct application of BDNF exerts a protective effect against Aβ-related pathologies. We investigated the therapeutic effects of BDNF on tauopathy in a P301L mouse model, using an adenoassociated virus (AAV)-mediated delivery method

Methods

Results

Conclusion