title: Cerebral microvascular rather than parenchymal amyloid-β protein pathology promotes early cognitive impairment in transgenic mice.
abstract: Alzheimer's disease (AD) is an age-dependent neurodegenerative condition that causes a progressive decline in cognitive function. Accumulation of amyloid β-protein (Aβ) in the brain is a prominent feature of AD and related disorders. However, the levels of Aβ accumulation alone are not a reliable predictor of cognitive deficits. Aβ accumulates in AD brain in the form of parenchymal amyloid plaques and cerebral vascular deposits. Although both types of lesions can contribute to cognitive decline, their temporal impact remains unclear. Moreover, cerebral microvascular pathology is identified as an early driver of cognitive impairment. Here for the first time, we compared two transgenic mouse strains, Tg-5xFAD and Tg-SwDI, which exhibit similar onset and anatomical accumulation of Aβ, but with distinct parenchymal and microvascular compartmental deposition, respectively, to assess their impact on cognitive impairment. Cohorts of each line were tested at 3 and 6 months of age to assess the relationship between spatial working memory performance and quantitative pathology. At 3 months of age, Tg-SwDI mice with onset of cerebral microvascular amyloid were behaviorally impaired, while the Tg-5xFAD, which had disproportionately higher levels of total Aβ, soluble oligomeric Aβ, and parenchymal amyloid were not. However, at 6 months of age, behavioral deficits for both groups of transgenic mice were evident, as the levels of Aβ pathologies in the Tg-5xFAD accumulated to extremely high amounts. The present findings suggest early-onset cerebral microvascular amyloid deposition, that precedes high parenchymal levels of Aβ, may be an important early factor in the development of cognitive deficits.
authors.affiliation: Department of Psychology, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Wenjin
authors.initials: W
authors.lastname: Xu
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.forename: Maria E
authors.initials: ME
authors.lastname: Anderson
authors.forename: AnnMarie E
authors.initials: AE
authors.lastname: Kotarba
authors.forename: Judianne
authors.initials: J
authors.lastname: Davis
authors.forename: John K
authors.initials: JK
authors.lastname: Robinson
authors.forename: William E
authors.initials: WE
authors.lastname: Van Nostrand
mesh_terms: D000367:Age Factors; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology*; D060825:Cognitive Dysfunction / Q000235:genetics / Q000473:pathology*; D006801:Humans; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D055806:Microvessels / Q000378:metabolism / Q000473:pathology*; D010446:Peptide Fragments / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics; D011930:Reaction Time / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053327:Apolipoprotein E4; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)
keywords: Amyloid-β protein; cerebral microvascular; cognitive impairment; parenchymal; pathology; transgenic mice
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