title: Short-term modern life-like stress exacerbates Aβ-pathology and synapse loss in 3xTg-AD mice.
abstract: Alzheimer's disease (AD) is a progressive neurological disorder that impairs memory and other cognitive functions in the elderly. The social and financial impacts of AD are overwhelming and are escalating exponentially as a result of population aging. Therefore, identifying AD-related risk factors and the development of more efficacious therapeutic approaches are critical to cure this neurological disorder. Current epidemiological evidence indicates that life experiences, including chronic stress, are a risk for AD. However, it is unknown if short-term stress, lasting for hours, influences the onset or progression of AD. Here, we determined the effect of short-term, multi-modal 'modern life-like' stress on AD pathogenesis and synaptic plasticity in mice bearing three AD mutations (the 3xTg-AD mouse model). We found that combined emotional and physical stress lasting 5 h severely impaired memory in wild-type mice and tended to impact it in already low-performing 3xTg-AD mice. This stress reduced the number of synapse-bearing dendritic spines in 3xTg-AD mice and increased Aβ levels by augmenting AβPP processing. Thus, short-term stress simulating modern-life conditions may exacerbate cognitive deficits in preclinical AD by accelerating amyloid pathology and reducing synapse numbers. Epidemiological evidence indicates that life experiences, including chronic stress, are a risk for Alzheimer disease (AD). However, it is unknown if short stress in the range of hours influences the onset or progression of AD. Here, we determined the effect of short, multi-modal 'modern-lifelike'stress on AD pathogenesis and synaptic plasticity in mice bearing three AD mutations (the 3xTg-AD mouse model). We found that combined emotional and physical stress lasting 5 h severely impaired memory in wild-type mice and tended to impact it in already low-performing 3xTg-AD mice. This stress reduced the number of synapse-bearing dendritic spines in 3xTg-AD mice and increased Aβ levels by augmenting AβPP processing. Thus, short stress simulating modern-life conditions may exacerbate cognitive deficits in preclinical AD by accelerating amyloid pathology and reducing synapse numbers.
authors.affiliation: Department of Neurobiology and Behavior and Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Baglietto-Vargas
authors.affiliation: Department of Pediatrics, University of California, Irvine, California, USA.
authors.forename: Yuncai
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Neurobiology and Behavior and Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, USA.
authors.forename: Dongjin
authors.initials: D
authors.lastname: Suh
authors.affiliation: Department of Neurobiology and Behavior and Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, USA.
authors.forename: Rahasson R
authors.initials: RR
authors.lastname: Ager
authors.affiliation: Department of Neurobiology and Behavior and Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, USA.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Rodriguez-Ortiz
authors.affiliation: Department of Neurobiology and Behavior and Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, USA.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Medeiros
authors.affiliation: Department of Neurobiology and Behavior and Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, USA.
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Myczek
authors.affiliation: Department of Neurobiology and Behavior and Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, USA.
authors.forename: Kim N
authors.initials: KN
authors.lastname: Green
authors.affiliation: Department of Pediatrics, University of California, Irvine, California, USA.|Department of Anatomy/Neurobiology, University of California, Irvine, California, USA.
authors.forename: Tallie Z
authors.initials: TZ
authors.lastname: Baram
authors.affiliation: Department of Neurobiology and Behavior and Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, USA.
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000502:physiology; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004644:Emotions; D005106:Exploratory Behavior; D005938:Glucocorticoids / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009473:Neuronal Plasticity; D009622:Noise / Q000009:adverse effects*; D021641:Recognition, Psychology; D013315:Stress, Psychological / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D013569:Synapses / Q000473:pathology; D014732:Vibration / Q000009:adverse effects*; D016875:tau Proteins / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D005938:Glucocorticoids; C054369:MAPT protein, human; D016875:tau Proteins; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone
keywords: Alzheimer's disease; amyloid; dementia; dendritic spines; hippocampus; stress