title: Vascular and parenchymal amyloid pathology in an Alzheimer disease knock-in mouse model: interplay with cerebral blood flow.
abstract: BACKGROUND
  Accumulation and deposition of β-amyloid peptides (Aβ) in the brain is a central event in the pathogenesis of Alzheimer's disease (AD). Besides the parenchymal pathology, Aβ is known to undergo active transport across the blood-brain barrier and cerebral amyloid angiopathy (CAA) is a prominent feature in the majority of AD. Although impaired cerebral blood flow (CBF) has been implicated in faulty Aβ transport and clearance, and cerebral hypoperfusion can exist in the pre-clinical phase of Alzheimer's disease (AD), it is still unclear whether it is one of the causal factors for AD pathogenesis, or an early consequence of a multi-factor condition that would lead to AD at late stage. To study the potential interaction between faulty CBF and amyloid accumulation in clinical-relevant situation, we generated a new amyloid precursor protein (APP) knock-in allele that expresses humanized Aβ and a Dutch mutation in addition to Swedish/London mutations and compared this line with an equivalent knock-in line but in the absence of the Dutch mutation, both crossed onto the PS1M146V knock-in background.
  
  
  RESULTS
  Introduction of the Dutch mutation results in robust CAA and parenchymal Aβ pathology, age-dependent reduction of spatial learning and memory deficits, and CBF reduction as detected by fMRI. Direct manipulation of CBF by transverse aortic constriction surgery on the left common carotid artery caused differential changes in CBF in the anterior and middle region of the cortex, where it is reduced on the left side and increased on the right side. However these perturbations in CBF resulted in the same effect: both significantly exacerbate CAA and amyloid pathology.
  
  
  CONCLUSIONS
  Our study reveals a direct and positive link between vascular and parenchymal Aβ; both can be modulated by CBF. The new APP knock-in mouse model recapitulates many symptoms of AD including progressive vascular and parenchymal Aβ pathology and behavioral deficits in the absence of APP overexpression.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Li
authors.forename: Qinxi
authors.initials: Q
authors.lastname: Guo
authors.forename: Taeko
authors.initials: T
authors.lastname: Inoue
authors.forename: Vinicia A
authors.initials: VA
authors.lastname: Polito
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Tabuchi
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hammer
authors.forename: Robia G
authors.initials: RG
authors.lastname: Pautler
authors.forename: George E
authors.initials: GE
authors.lastname: Taffet
authors.affiliation: Huffington Center on Aging, Baylor College of Medicine, Houston, Texas 77030, USA. huiz@bcm.edu.
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D016657:Cerebral Amyloid Angiopathy / Q000378:metabolism / Q000473:pathology*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D055879:Gene Knock-In Techniques; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D051379:Mice
chemical_list: D016229:Amyloid beta-Peptides
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