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.