Late-long-term potentiation magnitude, but not Ab levels and amyloid pathology, is associated with behavioral performance in a rat knock-in model of Alzheimer disease.
Cleavage of Amyloid precursor protein by β- and γ-secretases lead to Ab formation. The widely accepted pathogenic model states that these mutations cause AD via an increase in Ab formation and accumulation of Ab in Amyloid plaques. APP mutations cause early onset familial forms of Alzheimer's diseas...
| Publicado en: | Frontiers in Aging Neuroscience Vol. 14; pp. 1 - 21 |
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| Autores principales: | , , , , , |
| Formato: | pictorial research tables/charts Journal Article |
| Publicado: |
Frontiers Media S.A.
11/11/2022
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=160475306&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 160475306 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 16634365 BG2U jtl: Frontiers in Aging Neuroscience issn: 16634365 maglogo: N pubinfo: dt: 11/11/2022 vid: 14 pid: 40038 pub: Frontiers Media S.A. artinfo: ui: 160475306 160475306 160475306 10.3389/fnagi.2022.1040576 160475306 ppf: 1 ppct: 20 formats: tig: atl: Late-long-term potentiation magnitude, but not Ab levels and amyloid pathology, is associated with behavioral performance in a rat knock-in model of Alzheimer disease. aug: au: Yesiltepe, Metin Tao Yin Tambini, Marc D. Breuillaud, Lionel Zehntner, Simone P. D'Adamio, Luciano affil: Department of Pharmacology, Physiology & Neuroscience, New Jersey Medical School, Brain Health Institute, Jacqueline Krieger Klein Center in Alzheimer's Disease and Neurodegeneration Research, Rutgers, The State University of New Jersey, Newark, NJ, United States sug: subj: Alzheimer's Disease Amyloids Blood Behavior, Animal Evaluation Neuropsychological Tests Mutation Genetic Techniques Task Performance and Analysis Animal Studies Rats Funding Source Spatial Perception Cognitive Flexibility Brain Physiology Neuroinflammation Memory Genotype Enzyme-Linked Immunosorbent Assay Blotting, Western Immunohistochemistry Electrophysiology ab: Cleavage of Amyloid precursor protein by β- and γ-secretases lead to Ab formation. The widely accepted pathogenic model states that these mutations cause AD via an increase in Ab formation and accumulation of Ab in Amyloid plaques. APP mutations cause early onset familial forms of Alzheimer's disease (FAD) in humans. We generated App-Swedish (Apps) knock-in rats, which carry a pathogenic APP mutation in the endogenous rat App gene. This mutation increases β-secretase processing of APP leading to both augmented Ab production and facilitation of glutamate release in Apps=s rats, via a β-secretase and APP-dependent glutamate release mechanism. Here, we studied 11 to 14-month-old male and female Apps=s rats. To determine whether the Swedish App mutation leads to behavioral deficits, Apps=s knock-in rats were subjected to behavioral analysis using the IntelliCage platform, an automated behavioral testing system. This system allows behavioral assessment in socially housed animals reflecting a more natural, less stress-inducing environment and eliminates experimenter error and bias while increasing precision of measurements. Surprisingly, a spatial discrimination and flexibility task that can reveal deficits in higher order brain function showed that Apps=s females, but not Apps=s male rats, performed significantly worse than same sex controls. Moreover, female control rats performed significantly better than control and Apps=s male rats. The Swedish mutation causes a significant increase in Ab production in 14-month-old animals of both sexes. Yet, male and female Apps=s rats showed no evidence of AD-related amyloid pathology. Finally, Apps=s rats did not show signs of significant neuroinflammation. Given that the APP Swedish mutation causes alterations in glutamate release, we analyzed Long-term potentiation (LTP), a long-lasting form of synaptic plasticity that is a cellular basis for learning and memory. Strikingly, LTP was significantly increased in Apps=s control females compared to both Apps=s sexes and control males. In conclusion, this study shows that behavioral performances are sex and App-genotype dependent. In addition, they are associated with LTP values and not Aβ or AD-related pathology. These data, and the failures of anti-Ab therapies in humans, suggest that alternative pathways, such as those leading to LTP dysfunction, should be targeted for disease-modifying AD therapy. pubtype: Academic Journal doctype: pictorial research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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