Intranasal BMP9 Ameliorates Alzheimer Disease-Like Pathology and Cognitive Deficits in APP/PS1 Transgenic Mice.

Zigao Wang,Wenbin Wan,Xiaojing Bai,Hengbing Zu,Lijie Duan,Lu Xiong

doi:10.3389/fnmol.2017.00032

Abstract

Alzheimer’s disease (AD) is the most common type of dementia and has no effective therapies. Previous studies showed that bone morphogenetic protein 9 (BMP9), an important factor in the differentiation and phenotype maintenance of cholinergic neurons, ameliorated the cholinergic defects resulting from amyloid deposition. These findings suggest that BMP9 has potential as a therapeutic agent for AD. However, the effects of BMP9 on cognitive function in AD and its underlying mechanisms remain elusive. In the present study, BMP9 was delivered intranasally to 7-month-old APP/PS1 mice for 4 weeks. Our data showed that intranasal BMP9 administration significantly improved the spatial and associative learning and memory of APP/PS1 mice. We also found that intranasal BMP9 administration significantly reduced the amyloid β (Aβ) plaques overall, inhibited tau hyperphosphorylation, and suppressed neuroinflammation in the transgenic mouse brain. Furthermore, intranasal BMP9 administration significantly promoted the expression of low-density lipoprotein receptor-related protein 1 (LRP1), an important membrane receptor involved in the clearance of amyloid β via the blood-brain barrier (BBB), and elevated the phosphorylation levels of glycogen synthase kinase-3β (Ser9), which is considered the main kinase involved in tau hyperphosphorylation. Our results suggest that BMP9 may be a promising candidate for treating AD by targeting multiple key pathways in the disease pathogenesis.

Highlights

Alzheimer’s disease (AD), the most common type of dementia among the elderly, is characterized clinically by progressive memory loss and other cognitive dysfunctions and pathologically by extracellular amyloid β (Aβ) plaques, intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau, together with the loss of neurons and synapses (Citron, 2010)
We found that the intranasal administration of bone morphogenetic protein 9 (BMP9) significantly reduced the amyloid plaque load and Aβ levels in the brains of amyloid precursor protein (APP)/PS1 mice, probably by promoting the efflux of Aβ mediated by lipoprotein receptor-related protein 1 (LRP1)
Our results suggest that BMP9 ameliorates cognitive impairments in AD by targeting multiple key pathways in the disease pathogenesis

Summary

Introduction

Alzheimer’s disease (AD), the most common type of dementia among the elderly, is characterized clinically by progressive memory loss and other cognitive dysfunctions and pathologically by extracellular amyloid β (Aβ) plaques, intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau, together with the loss of neurons and synapses (Citron, 2010). A great amount of evidence suggests that the extracellular accumulation, aggregation, and deposition of Aβ play pivotal roles in the pathogenesis of AD by triggering subsequent pathological events, such as tau hyperphosphorylation, BMP9 Ameliorates AD-Associated Cognitive Deficits neuroinflammation, oxidative stress, neuronal loss and synaptic degeneration These secondary pathological events accelerate the progression of AD (Hardy and Higgins, 1992; Tanzi and Bertram, 2005; Bettens et al, 2013). Tau aggregation inhibitors showed no substantial effects against memory decline in AD patients (Gauthier et al, 2016) These failed clinical trials suggest that targeting amyloid plaques or tau aggregation alone might be insufficient to halt the progression of dementia in AD. Multi-target drugs may be the alternative treatments for AD

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Conclusion