Prion protein regulates amyloid-beta induced dendritic spine pathology in a mouse model of Alzheimer's disease [electronic resource].

9781369099744

1 online resource (168 p.)

Access is available to the Yale community.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive decline and memory dysfunction, with synaptic loss being crucial to manifest symptoms. To better understand synapse loss in AD, we analyzed the turnover of dendritic spines as the postsynaptic specializations of excitatory synapses in the somatosensory cortex of APPswe/PSen1DeltaE9 mice (APP/PS1) mice. I compared young mice with intact synapse density, normal memory, absence of AR plaques and no inflammation to aged mice with memory deficits and synapse loss. I observed prominent increases in dendritic spine turnover for both 3 month and 10 month old APP/PS1 mice as compared to wild-type (WT). The APP/PS1 dysregulation requires cellular prion protein (PrPc) and occurs in the presence of soluble PrPc-interacting Abeta oligomers. In contrast to WT, the APP/PS1 mice lack responsiveness of spine dynamics to sensory stimulation, even though whisker-dependent experience achieves c-fos induction in barrel cortex after environmental enrichment. Critically, the PrPc-dependent enhancement of spine turnover of APP/PS1 is coupled with a net loss of persistent spines both early and late. To evaluate mechanisms of the experience-independent supranormal dendritic spine turnover in this AD model, I analyzed the transcriptome of young APP/PS1 mouse brain at an age when spine turnover is altered but synapse density and memory are normal, and Abeta plaque and inflammation are absent. Early expression changes occur for synaptic and lipid-metabolizing genes, and are PrPc-dependent. Thus, pathologic synaptic dysregulation underlying AD begins at a young age, and depends on PrPc signaling.

Books / Online / Dissertations & Theses

English

January 19, 2017

Thesis (Ph.D.)--Yale University, 2016.

Yale University.