Neuron and synapse loss are important features of the neuropathology of Alzheimer's disease (AD). Recently, we observed substantial age-related hippocampal neuron loss in APP751SL/PS1M146L transgenic mice but not in PS1M146L mice. Here, we investigated APP751SL mice, PS1M146L mice, and APP751SL/PS1M146L mice for age-related alterations in synaptic integrity within hippocampal stratum moleculare of the dentate gyrus (SM), stratum lucidum of area CA3 (SL), and stratum radiatum of area CA1-2 (SR) by analyzing densities and numbers of synaptophysin-immunoreactive presynaptic boutons (SIPBs). Wild-type mice, APP751SL mice and PS1M146L mice showed similar amounts of age-related SIPB loss within SM, and no SIPB loss within SL. Both APP751SL mice and PS1M146L mice showed age-related SIPB loss within SR. Importantly, APP751SL/PS1M146L) mice displayed the severest age-related SIPB loss within SM, SL, and SR, even in regions free of extracellular Abeta deposits. Together, these mouse models offer a unique framework to study the impact of several molecular and cellular events caused by mutant APP and/or mutant PS1 on age-related alterations in synaptic integrity. The observation of age-related SIPB loss within SR of PS1M146L mice supports a role of mutant PS1 in neurodegeneration apart from its contribution to alterations in Abeta generation.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1603440 | PMC |
| http://dx.doi.org/10.1016/S0002-9440(10)62963-X | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Early neuronal loss and axonal/presynaptic damage is associated with accelerated amyloid-β accumulation in AβPP/PS1 Alzheimer's disease mice subiculum.
J Alzheimers Dis
July 2015
Department Biología Celular, Genética y Fisiología, Facultad de Ciencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
The progressive cognitive decline leading to dementia in Alzheimer's disease (AD) patients is the consequence of a severe loss of synapses and neurons affecting particular cell subpopulations in selected brain areas, with the subiculum being one of the earliest regions displaying severe atrophy and pathology. The lack of significant neuronal loss in most AD models is, in fact, the major shortcoming for the preclinical evaluation of drugs that could have greater potential in patients to alleviate or prevent this disease. In this study, using immunohistochemical and stereological approaches, we have analyzed the histopathological events in the subiculum of AβPP751SwedLondon/PS1M146L mice, a transgenic model that displays neuronal vulnerability at early ages in hippocampus and entorhinal cortex.
View Article and Find Full Text PDFDefects in mitochondrial dynamics and metabolomic signatures of evolving energetic stress in mouse models of familial Alzheimer's disease.
PLoS One
July 2012
Department of Molecular Pharmacology and Experimental Therapeutics and Neurology, Mayo Clinic, Rochester, Minnesota, United States of America.
Background: The identification of early mechanisms underlying Alzheimer's Disease (AD) and associated biomarkers could advance development of new therapies and improve monitoring and predicting of AD progression. Mitochondrial dysfunction has been suggested to underlie AD pathophysiology, however, no comprehensive study exists that evaluates the effect of different familial AD (FAD) mutations on mitochondrial function, dynamics, and brain energetics.
Methods And Findings: We characterized early mitochondrial dysfunction and metabolomic signatures of energetic stress in three commonly used transgenic mouse models of FAD.
Alzheimer's disease-linked presenilin mutation (PS1M146L) induces filamin expression and γ-secretase independent redistribution.
J Alzheimers Dis
August 2011
Harriet and John Wooten Laboratory for Alzheimer's Disease and Neurodegenerative Diseases Research, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
Presenilin mutations are linked to the early onset familial Alzheimer's disease (FAD) and lead to a range of neuronal changes, indicating that presenilins interact with multiple cellular pathways to regulate neuronal functions. In this report, we demonstrate the effects of FAD-linked presenilin 1 mutation (PS1M146L) on the expression and distribution of filamin, an actin cross-linking protein that interacts with PS1 both physically and genetically. By using immunohistochemical methods, we evaluated hippocampal dentate gyrus for alterations of proteins involved in synaptic plasticity.
View Article and Find Full Text PDFValidation of MRI-based 3D digital atlas registration with histological and autoradiographic volumes: an anatomofunctional transgenic mouse brain imaging study.
Neuroimage
July 2010
CEA-DSV-I2BM-MIRCen, CNRS URA2210, F-92265 Fontenay aux Roses Cedex, France.
Murine models are commonly used in neuroscience to improve our knowledge of disease processes and to test drug effects. To accurately study neuroanatomy and brain function in small animals, histological staining and ex vivo autoradiography remain the gold standards to date. These analyses are classically performed by manually tracing regions of interest, which is time-consuming.
View Article and Find Full Text PDFPresenilin 1-related alterations in DNA integrity in a transgenic mouse model of Alzheimer's disease.
Brain Res
February 2010
Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
The present study tested the hypothesis that mutations in amyloid precursor protein (APP) and presenilin (PS) 1 result in alterations in the amount of nuclear (n) DNA repair and nDNA damage in neurons in vivo. To this end, the relative amount of nDNA repair was measured in 8-month-old transgenic mice expressing either human mutant APP (APP751(SL) mice), human mutant PS1 (PS1(M146L) mice) or both human mutant APP and PS1 (APP751(SL)/PS1(M146L) mice) with unscheduled DNA synthesis, and the relative amount of nDNA single strand breaks (SSB) with in situ nick translation. APP751(SL)/PS1(M146L) mice showed a significantly decreased relative amount of nDNA repair in pyramidal cells in hippocampal area CA1/2 compared to APP751(SL) mice.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!