Alzheimer's disease (AD) is an age-related neurodegenerative disorder defined by the deposition of ?- amyloid (A?) plaques and neurofibrillary tangles (NFT), of which the principal components are A? peptides derived from the amyloid precursor protein (APP) and hyper-phosphorylated tau, respectively. The relationship between the extracellular A? and intracellular NFT pathologies and how they mediate synaptic dysfunction, which is regarded as a causal event in AD, remain poorly understood. Mutations in APP and presenilin (PSEN) genes lead to early onset of familial AD (FAD), establishing their critical roles in AD pathogenesis. Based on the genetic evidence, we have established APP and PS1 knockin mouse models (APP/hA?/PS1) in which the disease-causing mutations and human A? sequence are introduced into the endogenous APP or PSEN1 loci such that the pathogenic effects of the FAD mutations and A? can be investigated under their physiological context. Analysis of the knockin mice show that they exhibit profound anxiety phenotypes, likely mediated by impaired inhibitory neuronal function. We have now developed a second generation of the knockin mice which allow us to express the APP/PS1 mutations and A? in specific neurons and brain regions. Equipped with these powerful mouse models, the application seeks to gain mechanistic and functional understanding of AD pathogenesis by addressing the following fundamental questions: 1) What is the relationship between anxiety/stress and dementia? 2) How does the specific impairment of excitatory or inhibitory neurons contribute to synaptic dysregulation and whether they differentially mediate cognitive and stress-related behaviors? 3) What are the molecular and cellular mechanisms mediating mutant APP/hA?/PS1-induced NFT pathology? Our proposal will reveal unprecedented insights into AD pathogenesis and we are equipped with innovative and sophisticated mouse models to address these questions.
The objective of the application is to decipher AD pathogenesis at the cellular and network levels using novel and disease-relevant mouse models. It will lead to the mechanistic understanding of the pathways contributing to the neuropathological, synaptic and behavioral phenotypes and the identification of effective cellular targets for therapeutic intervention.
|Lian, Hong; Yang, Li; Cole, Allysa et al. (2015) NF?B-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer's disease. Neuron 85:101-15|
|Wang, Baiping; Wang, Zilai; Sun, Lu et al. (2014) The amyloid precursor protein controls adult hippocampal neurogenesis through GABAergic interneurons. J Neurosci 34:13314-25|
|Li, Hongmei; Guo, Qinxi; Inoue, Taeko et al. (2014) Vascular and parenchymal amyloid pathology in an Alzheimer disease knock-in mouse model: interplay with cerebral blood flow. Mol Neurodegener 9:28|
|Polito, Vinicia A; Li, Hongmei; Martini-Stoica, Heidi et al. (2014) Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB. EMBO Mol Med 6:1142-60|
|Wang, Zilai; Yang, Li; Zheng, Hui (2012) Role of APP and Aýý in synaptic physiology. Curr Alzheimer Res 9:217-26|
|Guo, Qinxi; Wang, Zilai; Li, Hongmei et al. (2012) APP physiological and pathophysiological functions: insights from animal models. Cell Res 22:78-89|
|Barbagallo, Alessia P M; Wang, Zilai; Zheng, Hui et al. (2011) A single tyrosine residue in the amyloid precursor protein intracellular domain is essential for developmental function. J Biol Chem 286:8717-21|
|Barbagallo, Alessia P M; Wang, Zilai; Zheng, Hui et al. (2011) The intracellular threonine of amyloid precursor protein that is essential for docking of Pin1 is dispensable for developmental function. PLoS One 6:e18006|
|Wang, Baiping; Harrison, Wilbur; Overbeek, Paul A et al. (2011) Transposon mutagenesis with coat color genotyping identifies an essential role for Skor2 in sonic hedgehog signaling and cerebellum development. Development 138:4487-97|
|Hernandez, Caterina M; Kayed, Rakez; Zheng, Hui et al. (2010) Loss of alpha7 nicotinic receptors enhances beta-amyloid oligomer accumulation, exacerbating early-stage cognitive decline and septohippocampal pathology in a mouse model of Alzheimer's disease. J Neurosci 30:2442-53|
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