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Hypertension, cerebrovascular impairment, and cognitive decline in aged AβPP/PS1 mice
Maximilian Wiesmann1, Valerio Zerbi2, Diane Jansen1
1Radboud university medical center, Donders Institute for Brain, Cognition & Behaviour, Radboud Alzheimer Center, Department of Anatomy, Preclinical Imaging Centre PRIME, Nijmegen, The Netherlands.
Insights
High blood pressure in aging mice with Alzheimer's disease (AD) correlates with reduced brain blood flow, impaired brain connectivity, and cognitive decline. This model offers insights into early AD development and potential treatments.
Area of Science:
- Neuroscience
- Cardiovascular Research
- Alzheimer's Disease Pathogenesis
Background:
- Hypertension is a significant risk factor for Alzheimer's disease (AD).
- Understanding the vascular contributions to neurodegeneration is crucial for early AD intervention.
Purpose of the Study:
- To investigate the relationship between systolic blood pressure (SBP), cerebral blood flow (CBF), and brain changes in an aging mouse model of AD.
- To explore the vascular origins of neurodegenerative processes in Alzheimer's disease.
Main Methods:
- Utilized a double transgenic AβPPswe/PS1dE9 mouse model for AD.
- Employed advanced MRI techniques to assess cerebral blood flow, brain connectivity, and structure.
- Conducted post-mortem analyses for neuroinflammation, synaptogenesis, and neurogenesis.
Main Results:
- Aging AβPP/PS1 mice exhibited increased SBP, decreased regional CBF, and impaired functional/structural brain connectivity.
- Cognitive deficits, increased locomotor activity, and anxiety-like behaviors were observed in AD-like mice.
- Elevated neuroinflammation, reduced synaptogenesis/neurogenesis, and altered brain fatty acid metabolism were noted.
Conclusions:
- Increased SBP is linked to reduced cerebral hemodynamics and connectivity in an aging AD mouse model, contributing to cognitive and behavioral impairments.
- The findings mirror early-stage AD symptomatology, suggesting the model's utility for studying prevention and treatment strategies.
- This research aids in developing better diagnostics and therapies for the prodromal phase of Alzheimer's disease.
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.
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