Dentate gyrus volume is reduced before onset of plaque formation in PDAPP mice: A magnetic resonance microscopy and stereologic analysis
Jeffrey M. Redwine,Barry E. Kosofsky,Russell E. Jacobs,Dora Games,John F. Reilly,John H. Morrison,Warren G. Young,Floyd E. Bloom +7 more
TLDR
It is concluded that overexpression of APP and amyloid may initiate pathologic changes before the appearance of plaques, suggesting novel targets for the treatment of Alzheimer's disease and further reinforcing the need for early diagnosis and treatment.Abstract:
High-resolution magnetic resonance microscopy (MRM) was used to determine regional brain volumetric changes in a mouse model of Alzheimer's disease. These transgenic (Tg) mice overexpress human mutant amyloid precursor protein (APP) V717F under control of platelet-derived growth factor promoter (PDAPP mice), and cortical and hippocampal beta-amyloid (Abeta) deposits accumulate in heterozygotes after 8-10 mos. We used MRM to obtain 3D volumetric data on mouse brains imaged in their skulls to define genotype- and age-related changes. Hippocampal, cerebellar, and brain volumes and corpus callosum length were quantified in 40-, 100-, 365-, and 630-day-old mice. Measurements taken at age 100 days, before A(beta) deposition, revealed a 12.3% reduction of hippocampus volume in Tg mice compared with WT controls. This reduction persisted without progression to age 21 mos. A significant 18% increase in hippocampal volume occurred between 40 and 630 days in WT mice, and no corresponding significant increase occurred in Tg mice. Cavalieri volume estimates of hippocampal subfields from 100-day-old Tg mice further localized a 28% volume deficit in the dentate gyrus. In addition, corpus callosum length was reduced by approximate to 25% in Tg mice at all ages analyzed. In summary, reduced hippocampal volume and corpus callosum length can be detected by MIRM before Abeta deposition. We conclude that overexpression of APP and amyloid may initiate pathologic changes before the appearance of plaques, suggesting novel targets for the treatment of Alzheimer's disease and further reinforcing the need for early diagnosis and treatment.read more
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Molecular, Structural, and Functional Characterization of Alzheimer's Disease: Evidence for a Relationship between Default Activity, Amyloid, and Memory
Randy L. Buckner,Abraham Z. Snyder,Benjamin J. Shannon,Gina N. LaRossa,Rimmon Sachs,Anthony F. Fotenos,Yvette I. Sheline,William E. Klunk,Chester A. Mathis,John C. Morris,Mark A. Mintun +10 more
TL;DR: One possibility is that lifetime cerebral metabolism associated with regionally specific default activity predisposes cortical regions to AD-related changes, including amyloid deposition, metabolic disruption, and atrophy, which may be part of a network with the medial temporal lobe whose disruption contributes to memory impairment.
Journal ArticleDOI
Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease.
Gorazd B. Stokin,Concepción Lillo,Tomás L. Falzone,Richard G. Brusch,Edward Rockenstein,Stephanie L. Mount,Rema Raman,Peter Davies,Eliezer Masliah,David S. Williams,Lawrence S.B. Goldstein +10 more
TL;DR: Reductions in microtubule-dependent transport may stimulate proteolytic processing of β-amyloid precursor protein, resulting in the development of senile plaques and Alzheimer's disease.
Journal ArticleDOI
Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease
J. Steven Jacobsen,Chi-Cheng Wu,Jeffrey M. Redwine,Thomas A. Comery,Robert L. Arias,Mark R. Bowlby,Robert Martone,John H. Morrison,Menelas N. Pangalos,Peter H. Reinhart,Floyd E. Bloom +10 more
TL;DR: Overall, these data show that the perforant path input from the entorhinal cortex to the DG is compromised both structurally and functionally, and this pathology is manifested in memory defects long before significant plaque deposition.
Journal ArticleDOI
High resolution three-dimensional brain atlas using an average magnetic resonance image of 40 adult C57Bl/6J mice
TL;DR: A three-dimensional atlas of the mouse brain, manually segmented into 62 structures, based on an average of 32 mum isotropic resolution T(2)-weighted, within skull images of forty 12 week old C57Bl/6J mice, scanned on a 7 T scanner is described.
Journal ArticleDOI
The aging brain: morphomolecular senescence of cortical circuits
Patrick R. Hof,John H. Morrison +1 more
TL;DR: Animal studies suggest that both AD and age-associated cognitive impairment reflect vulnerability of the same circuits, however, neuron death predominates in the former, whereas the latter is probably mediated by synaptic alterations in otherwise intact circuits.
References
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John Hardy,Dennis J. Selkoe +1 more
TL;DR: It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid β-peptide in plaques in brain tissue and the rest of the disease process is proposed to result from an imbalance between Aβ production and Aβ clearance.
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Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein.
Dora Games,David S. Adams,Ree Alessandrini,Robin Barbour,Patricia Borthelette,Catherine Blackwell,Tony Carr,J. C. Clemens,Thomas Donaldson,Frances Gillespie,Terry Guido,Stephanie Hagopian,Kelly Johnson-Wood,Karen Khan,Michael K. Lee,Paul Leibowitz,Ivan Lieberburg,Sheila P. Little,Eliezer Masliah,Lisa McConlogue,Martin Montoya-Zavala,Lennart Mucke,Lisa Paganini,Elizabeth Penniman,Michael Power,Dale Schenk,Peter Seubert,Ben W. Snyder,Ferdie Soriano,Hua Tan,James Vitale,Sam Wadsworth,Ben Wolozin,Jun Zhao +33 more
TL;DR: Transgenic mice that express high levels of human mutant APP support a primary role for APP/Aβ in the genesis of AD and could provide a preclinical model for testing therapeutic drugs.
Journal ArticleDOI
Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease.
D. Scheuner,Christopher B. Eckman,Christopher B. Eckman,Malene Jensen,X. Song,Martin Citron,Nobuhiro Suzuki,Thomas D. Bird,John Hardy,Mike Hutton,Walter A. Kukull,Eric Larson,Ephrat Levy-Lahad,Matti Viitanen,Elaine R. Peskind,Parvoneh Poorkaj,Gerard D. Schellenberg,Rudolph E. Tanzi,Wilma Wasco,Lars Lannfelt,Dennis J. Selkoe,Steven G. Younkin +21 more
TL;DR: The findings indicate that the FAD–linked mutations may all cause Alzheimer's disease by increasing the extracellular concentration of Aβ42(43), thereby fostering cerebral deposition of this highly amyloidogenic peptide.
Journal ArticleDOI
Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease.
Frederique Bard,Catherine Cannon,Robin Barbour,Rae Lyn Burke,Dora Games,Henry Grajeda,Teresa Guido,Kang Hu,Jiping Huang,Kelly Johnson-Wood,Karen Khan,Dora Kholodenko,Michael K. Lee,Ivan Lieberburg,Ruth Motter,Minh Nguyen,Ferdie Soriano,Vasquez Nicki J,Kim Weiss,Brent Welch,Peter Seubert,Dale Schenk,Ted Yednock +22 more
TL;DR: Results indicate that antibodies can cross the blood–brain barrier to act directly in the central nervous system and should be considered as a therapeutic approach for the treatment of Alzheimer disease and other neurological disorders.
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