Apolipoprotein E isoform-specific regulation of dendritic spine morphology in apolipoprotein E transgenic mice and Alzheimer's disease patients

Abstract Background EphA4 is a receptor of the ephrin system regulating spine morphology and plasticity in the brain. These processes are pivotal in the pathophysiology of Alzheimer’s disease (AD), characterized by synapse dysfunction and loss, and the progressive loss of memory and other cognitive functions. Reduced EphA4 signaling has been shown to rescue beta-amyloid-induced dendritic spine loss and long-term potentiation (LTP) deficits in cultured hippocampal slices and primary hippocampal cultures. In this study, we investigated whether EphA4 ablation might preserve synapse function and ameliorate cognitive performance in the APPPS1 transgenic mouse model of AD. Methods A postnatal genetic ablation of EphA4 in the forebrain was established in the APPPS1 mouse model of AD, followed by a battery of cognitive tests at 9 months of age to investigate cognitive function upon EphA4 loss. A Golgi-Cox staining was used to explore alterations in dendritic spine density and morphology in the CA1 region of the hippocampus. Results Upon EphA4 loss in APPPS1 mice, we observed improved social memory in the preference for social novelty test without affecting other cognitive functions. Dendritic spine analysis revealed altered synapse morphology as characterized by increased dendritic spine length and head width. These modifications were independent of hippocampal plaque load and beta-amyloid peptide levels since these were similar in mice with normal versus reduced levels of EphA4. Conclusion Loss of EphA4 improved social memory in a mouse model of Alzheimer’s disease in association with alterations in spine morphology.

Download Full-text

Collapsin Response Mediator Proteins: Novel Targets for Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-200721 ◽

2020 ◽

Vol 77 (3) ◽

pp. 949-960 ◽

Cited By ~ 1

Author(s):

Tam T. Quach ◽

Aubin Moutal ◽

Rajesh Khanna ◽

Nicholas P. Deems ◽

Anne-Marie Duchemin ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Axon Guidance ◽

Immune Cells ◽

Dendritic Growth ◽

Therapeutic Interventions ◽

Spine Morphology ◽

Dendritic Spine Morphology ◽

Postmortem Studies ◽

Novel Targets

Numerous experimental and postmortem studies have increasingly reported dystrophic axons and dendrites, and alterations of dendritic spine morphology and density in the hippocampus as prominent changes in the early stages of Alzheimer’s disease (AD). Furthermore, these alterations tend to correlate well with the progressive cognitive decline observed in AD. For these reasons, and because these neurite structures have a capacity to re-grow, re-establish lost connections, and are critical for learning and memory, there is compelling evidence to suggest that therapeutic interventions aimed at preventing their degradation or promoting their regrowth may hold tremendous promise in preventing the progression of AD. In this regard, collapsin response mediator proteins (CRMPs), a family of phosphoproteins playing a major role in axon guidance and dendritic growth, are especially interesting. The roles these proteins play in neurons and immune cells are reviewed here.

Download Full-text

Rapamycin rescues vascular, metabolic and learning deficits in apolipoprotein E4 transgenic mice with pre-symptomatic Alzheimer’s disease

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x15621575 ◽

2016 ◽

Vol 37 (1) ◽

pp. 217-226 ◽

Cited By ~ 61

Author(s):

Ai-Ling Lin ◽

Jordan B Jahrling ◽

Wei Zhang ◽

Nicholas DeRosa ◽

Vikas Bakshi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Apolipoprotein E ◽

Late Onset ◽

Human Subjects ◽

Susceptibility Gene ◽

Learning Deficits ◽

Cerebrovascular Function

Apolipoprotein E ɛ4 allele is a common susceptibility gene for late-onset Alzheimer's disease. Brain vascular and metabolic deficits can occur in cognitively normal apolipoprotein E ɛ4 carriers decades before the onset of Alzheimer's disease. The goal of this study was to determine whether early intervention using rapamycin could restore neurovascular and neurometabolic functions, and thus impede pathological progression of Alzheimer's disease-like symptoms in pre-symptomatic Apolipoprotein E ɛ4 transgenic mice. Using in vivo, multimodal neuroimaging, we found that apolipoprotein E ɛ4 mice treated with rapamycin had restored cerebral blood flow, blood–brain barrier integrity and glucose metabolism, compared to age- and gender-matched wild-type controls. The preserved vasculature and metabolism were associated with amelioration of incipient learning deficits. We also found that rapamycin restored the levels of the proinflammatory cyclophilin A in vasculature, which may contribute to the preservation of cerebrovascular function in the apolipoprotein E ɛ4 transgenics. Our results show that rapamycin improves functional outcomes in this mouse model and may have potential as an effective intervention to block progression of vascular, metabolic and early cognitive deficits in human Apolipoprotein E ɛ4 carriers. As rapamycin is FDA-approved and neuroimaging is readily used in humans, the results of the present study may provide the basis for future Alzheimer's disease intervention studies in human subjects.

Download Full-text