Theranostics 2017; 7(5):1277-1289. doi:10.7150/thno.18509

Research Paper

Hypertension, cerebrovascular impairment, and cognitive decline in aged AβPP/PS1 mice

Maximilian Wiesmann1, Valerio Zerbi2, Diane Jansen1, Dieter Lütjohann3, Andor Veltien4, Arend Heerschap4, Amanda J Kiliaan1✉

1. Radboud university medical center, Donders Institute for Brain, Cognition & Behaviour, Radboud Alzheimer Center, Department of Anatomy, Preclinical Imaging Centre PRIME, Nijmegen, The Netherlands.
2. Neural Control of Movement Lab, Department of Health Sciences and Technology, ETH Zurich, Switzerland.
3. Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
4. Radboud University Medical Center, Department of Radiology & Nuclear Medicine, Preclinical Imaging Centre PRIME, Nijmegen, The Netherlands.

Abstract

Cardiovascular risk factors, especially hypertension, are also major risk factors for Alzheimer's disease (AD). To elucidate the underlying vascular origin of neurodegenerative processes in AD, we investigated the relation between systolic blood pressure (SBP) cerebral blood flow (CBF) and vasoreactivity with brain structure and function in a 16-18 months old double transgenic AβPPswe/PS1dE9 (AβPP/PS1) mouse model for AD. These aging AβPP/PS1 mice showed an increased SBP linked to a declined regional CBF. Furthermore, using advanced MRI techniques, decline of functional and structural connectivity was revealed in the AD-like mice coupled to impaired cognition, increased locomotor activity, and anxiety-related behavior. Post mortem analyses demonstrated also increased neuroinflammation, and both decreased synaptogenesis and neurogenesis in the AβPP/PS1 mice. Additionally, deviant levels of fatty acids and sterols were present in the brain tissue of the AβPP/PS1 mice indicating maladapted brain fatty acid metabolism. Our findings suggest a link between increased SBP, decreased cerebral hemodynamics and connectivity in an AD mouse model during aging, leading to behavioral and cognitive impairments. As these results mirror the complex clinical symptomatology in the prodromal phase of AD, we suggest that this AD-like murine model could be used to investigate prevention and treatment strategies for early AD patients. Moreover, this study helps to develop more efficient therapies and diagnostics for this very early stage of AD.

Keywords: Blood pressure, Cerebral blood flow, Alzheimer's disease, Functional connectivity, Neuropathology, Neurodegeneration: experimental models.

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How to cite this article:
Wiesmann M, Zerbi V, Jansen D, Lütjohann D, Veltien A, Heerschap A, Kiliaan AJ. Hypertension, cerebrovascular impairment, and cognitive decline in aged AβPP/PS1 mice. Theranostics 2017; 7(5):1277-1289. doi:10.7150/thno.18509. Available from http://www.thno.org/v07p1277.htm