TY - JOUR
T1 - Vascular and parenchymal amyloid pathology in an Alzheimer disease knock-in mouse model
T2 - Interplay with cerebral blood flow
AU - Li, Hongmei
AU - Guo, Qinxi
AU - Inoue, Taeko
AU - Polito, Vinicia A.
AU - Tabuchi, Katsuhiko
AU - Hammer, Robert E.
AU - Pautler, Robia G.
AU - Taffet, George
AU - Zheng, Hui
N1 - Funding Information:
We thank Dr. Thomas C. Südhof for initiating the project and his continuous support. We are grateful to C. Spencer and the Baylor College of Medicine IDDRC Administrative and Mouse Neurobehavioral cores (HD024064) for the generous resources and support. We are especially grateful to Dr. Thuy T. Pham and other members of Dr. George Taffet’s lab for their valuable expertise in TAC related experiments. We are grateful to Drs. Christine Beeton and Robert M. Bryan Jr. for their technical guidance and supports. We thank N. Aithmitti and A. Cole for expert technical assistance, Dr. Daniel Swartzlander for editing the manuscript, and members of Zheng lab for their constructive discussions. This work was supported by grants from NIH (AG020670, AG032051 and NS076117 to HZ) and fellowship from BrightFocus (A2013370F to HL).
Publisher Copyright:
© 2014 Li et al.; licensee BioMed Central Ltd.
PY - 2014/8/9
Y1 - 2014/8/9
N2 - 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.
AB - 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.
KW - Alzheimer disease
KW - Cerebral amyloid angiopathy (CAA)
KW - Cerebral blood flow (CBF)
KW - Dutch mutation
KW - Parenchymal plaque
KW - Transverse aortic constriction (TAC)
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U2 - 10.1186/1750-1326-9-28
DO - 10.1186/1750-1326-9-28
M3 - Article
C2 - 25108425
AN - SCOPUS:84906931766
VL - 9
JO - Molecular Neurodegeneration
JF - Molecular Neurodegeneration
SN - 1750-1326
IS - 1
M1 - 28
ER -