Dentate gyrus volume is reduced before onset of plaque formation in PDAPP mice: A magnetic resonance microscopy and stereologic analysis

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 ␤-amyloid (A␤) 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␤ 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 Ϸ25% in Tg mice at all ages analyzed. In summary, reduced hippocampal volume and corpus callosum length can be detected by MRM before A␤ 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.T he essential neuropathologic features of Alzheimer's disease (AD) include the progressive deposition of amyloid plaques and neurofibrillary tangles in neocortical and hippocampal structures and a parallel global decrease in cortical volume (1, 2). Extensive data from analysis of postmortem human brain and mouse models of AD associate the neuropathology of AD with alterations in the expression, distribution, and deposition of ␤ amyloid protein (A␤). In AD brains, A␤ levels are increased, and the protein can be found in fibrillar chains within compact plaques, aggregated in diffuse plaques, or as oligomers and monomers in regions outside of plaques (3-6). Some of the known human mutations associated with AD affect the processing or cleavage of amyloid precursor protein (APP) and can cause increased A␤ levels or increase the relative amount of the primary plaque component A␤ 1-42 compared with A␤ 1-40 (3, 5-10). Other human mutations have been identified within the coding region of A␤ 1-42 , which can increase A␤ neurotoxicity (11). Transgenic (Tg) mouse models have shown that high levels of A␤ can cause AD-like amyloid plaque pathology. Tg mice that overexpress APP have some but not all deficits observed in AD (12, 13). Other Tg mouse models that have mutations associated with AD resulting in up-regulation of A␤ production have many, but not all, of the observed deficits seen in AD, including reduced hippocampal volume, reduced synap...

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