Reduced cortical excitatory synapse number in APOE4 mice is associated with increased calcineurin activity

Neustadtl, Aidan; Winston, Charisse N.; Parsadanian, Maia; Main, Bevan S.; Villapol, Sonia; Burns, Mark P.

doi:10.1097/wnr.0000000000000811

Cited by 17 publications

(14 citation statements)

References 36 publications

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“…Various mechanisms have been proposed as to how APOE isoforms differentially regulate dendritic changes in AD. These range from altered binding of APOE to receptors and subsequent intracellular signalling cascades , impaired regulation of receptors within spines , elevations in calcineurin activity that is associated with reductions in spine density and impairments of neuronal outgrowth , among others.…”

Section: Results Of the Systematic Literature Searchmentioning

confidence: 99%

Invited Review: APOE at the interface of inflammation, neurodegeneration and pathological protein spread in Alzheimer's disease

Tzioras

Davies

Newman

et al. 2018

Neuropathology Appl Neurobio

102

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Despite more than a century of research, the aetiology of sporadic Alzheimer's disease ( AD ) remains unclear and finding disease modifying treatments for AD presents one of the biggest medical challenges of our time. AD pathology is characterized by deposits of aggregated amyloid beta (Aβ) in amyloid plaques and aggregated tau in neurofibrillary tangles. These aggregates begin in distinct brain regions and spread throughout the brain in stereotypical patterns. Neurodegeneration, comprising loss of synapses and neurons, occurs in brain regions with high tangle pathology, and an inflammatory response of glial cells appears in brain regions with pathological aggregates. Inheriting an apolipoprotein E ε4 ( APOE 4 ) allele strongly increases the risk of developing AD for reasons that are not yet entirely clear. Substantial amounts of evidence support a role for APOE in modulating the aggregation and clearance of Aβ, and data have been accumulating recently implicating APOE 4 in exacerbating neurodegeneration, tau pathology and inflammation. We hypothesize that APOE 4 influences all the pathological hallmarks of AD and may sit at the interface between neurodegeneration, inflammation and the spread of pathologies through the brain. Here, we conducted a systematic search of the literature and review evidence supporting a role for APOE 4 in neurodegeneration and inflammation. While there is no direct evidence yet for APOE 4 influencing the spread of pathology, we postulate that this may be found in future based on the literature reviewed here. In conclusion, this review highlights the importance of understanding the role of APOE in multiple important pathological mechanisms in AD .

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Section: Results Of the Systematic Literature Searchmentioning

confidence: 99%

Invited Review: APOE at the interface of inflammation, neurodegeneration and pathological protein spread in Alzheimer's disease

Tzioras

Davies

Newman

et al. 2018

Neuropathology Appl Neurobio

102

View full text Add to dashboard Cite

show abstract

“…Control APOE4 mice and showed increases in amyloid beta (Aβ)42 and tau staining and a decrease in VGlut levels compared to APOE3 mice [16]. APOE4 KI mice have decreased spine densities and synaptic integrity at several ages compared to APOE3 KI mice [10,17,18,19]. Similar decreases in spine densities have been seen in the medial entorhinal cortex of APOE4 mouse brains [20].…”

Section: Apoe4 and Admentioning

confidence: 90%

The Synergistic Effects of APOE Genotype and Obesity on Alzheimer’s Disease Risk

Jones

Rebeck

2018

IJMS

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The APOE gene has three common alleles—E2, E3, and E4, with APOE4 being the strongest genetic risk factor for developing Alzheimer’s Disease (AD). Obesity is a global epidemic and contributes to multiple metabolic problems. Obesity is also a risk factor for cognitive decline. Here, we review the effects of APOE4 and obesity on cognition and AD development, independently and together. We describe studies that have associated APOE4 with cognitive deficits and AD, as well as studies that have associated obesity to cognitive deficits and AD. We then describe studies that have examined the effects of obesity and APOE genotypes together, with a focus on APOE4 and high fat diets. Both human studies and rodent models have contributed to understanding the effects of obesity on the different APOE genotypes, and we outline possible underlying mechanisms associated with these effects. Data across approaches support a model in which APOE4 and obesity combine for greater detrimental effects on metabolism and cognition, in ways that are influenced by both age and sex.

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“…Taqman probes ( Supplemental Methods ) were analyzed under the following cycle conditions: 50 °C for 2 min, 95 °C for 20 s, (95 °C for 1 s, 60 °C for 20 s) with 40 cycles. SDS 2.4 software (Applied Biosystems) was used to generate threshold cycle (Ct) values, and fold change (FC) in mRNA expression was calculated using the ΔΔCt method (2 −ΔΔCt ) 89 , 90 .…”

Section: Methodsmentioning

confidence: 99%

High-frequency head impact causes chronic synaptic adaptation and long-term cognitive impairment in mice

et al. 2021

Self Cite

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Repeated head impact exposure can cause memory and behavioral impairments. Here, we report that exposure to non-damaging, but high frequency, head impacts can alter brain function in mice through synaptic adaptation. High frequency head impact mice develop chronic cognitive impairments in the absence of traditional brain trauma pathology, and transcriptomic profiling of mouse and human chronic traumatic encephalopathy brain reveal that synapses are strongly affected by head impact. Electrophysiological analysis shows that high frequency head impacts cause chronic modification of the AMPA/NMDA ratio in neurons that underlie the changes to cognition. To demonstrate that synaptic adaptation is caused by head impact-induced glutamate release, we pretreated mice with memantine prior to head impact. Memantine prevents the development of the key transcriptomic and electrophysiological signatures of high frequency head impact, and averts cognitive dysfunction. These data reveal synapses as a target of high frequency head impact in human and mouse brain, and that this physiological adaptation in response to head impact is sufficient to induce chronic cognitive impairment in mice.

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Reduced cortical excitatory synapse number in APOE4 mice is associated with increased calcineurin activity

Cited by 17 publications

References 36 publications

Invited Review: APOE at the interface of inflammation, neurodegeneration and pathological protein spread in Alzheimer's disease

Invited Review: APOE at the interface of inflammation, neurodegeneration and pathological protein spread in Alzheimer's disease

The Synergistic Effects of APOE Genotype and Obesity on Alzheimer’s Disease Risk

High-frequency head impact causes chronic synaptic adaptation and long-term cognitive impairment in mice

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