Early Activation of Experience-Independent Dendritic Spine Turnover in a Mouse Model of Alzheimer's Disease

Abstract

Synaptic loss is critical in Alzheimer's disease (AD), but the dynamics of synapse turnover are poorly defined. We imaged dendritic spines in transgenic APPswe/PSen1∆E9 (APP/PS1) cerebral cortex. Dendritic spine turnover is increased far from plaque in aged APP/PS1 mice, and in young APP/PS1 mice prior to plaque formation. Dysregulation occurs in the presence of soluble Aβ oligomer and requires cellular prion protein (PrPC). APP/PS1 mice lack responsiveness of spine turnover to sensory stimulation. Critically, enhanced spine turnover is coupled with the loss of persistent spines starting early and continuing with age. To evaluate mechanisms of experience-independent supranormal spine turnover, we analyzed the transcriptome of young APP/PS1 mouse brain when turnover is altered but synapse density and memory are normal, and plaque and inflammation are absent. Early PrPC-dependent expression changes occur in synaptic and lipid-metabolizing genes. Thus, pathologic synaptic dysregulation underlying AD begins at a young age prior to Aβ plaque.

Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network

“…There is also a further increase in expression of several TNG components in APP/PS1 Grn −/− mice, although we detect no significant changes in the TNG or pro-inflammatory or anti-inflammatory genes in APP/PS1 mice, in distinction to previous studies investigating neuroinfllammation in AD mouse models [68]. This discrepancy is likely explained by a difference in mouse age [33]. Many previous studies have used aged AD mouse models while we performed qRT-PCR analysis using 6-month-old animals.…”

Silent Allosteric Modulation of mGluR5 Maintains Glutamate Signaling while Rescuing Alzheimer’s Mouse Phenotypes

“…Aβo/PrP C -induced signaling via mGluR5 regulates multiple pathways (Haas et al, 2014, 2016; Haas and Strittmatter, 2016; Heiss et al, 2016; Kaufman et al, 2015; Um et al, 2012, 2013). Here, we show that Aβo-induced receptor interactions can be targeted specifically by silent allosteric modulation of mGluR5 without affecting physiological glutamate signaling and without EEG amplitude suppression, even at doses 10-fold higher than efficacious levels.…”

“…Synaptic recovery restores brain anatomy over 4 weeks and permits learning and memory improvements. Previously, we studied dendritic spine turnover in APP/PS1 mice compared with wild-type (WT) mice as a function of age and Prnp genotype (Heiss et al, 2016). The APP/PS1 transgene accelerates spine loss but does not impede the formation of new spines.…”

Cellular prion protein as a receptor for amyloid-β oligomers in Alzheimer's disease

“…Dendritic spine loss triggered by Aβo and observed by time lapse imaging in cultured hippocampal neurons, does not occur in neurons lacking PrP C [9-11]. Prnp null mice carrying an AD transgene do not exhibit the progressive synapse loss in the hippocampus observed in PrP C -intact AD transgenic mice [8, 12].…”

“…Prnp null mice carrying an AD transgene do not exhibit the progressive synapse loss in the hippocampus observed in PrP C -intact AD transgenic mice [8, 12]. In fact, by repeated in vivo imaging, dendritic spine dynamics are normalized in the AD transgenic mice when PrP C is absent [11]. Thus, in these models PrP C is essential for the deleterious effects of Aβo and AD transgenes on synaptic anatomy as well as physiology.…”