Document text
Principal Investigator: Ashley Elizabeth Walker
Organization: UNIVERSITY OF OREGON
Fiscal Year: 2024
Award: $398,361
Funding agency: National Institute on Aging
PROJECT SUMMARY
As the prevalence of late-onset Alzheimer’s disease continues to increase, understanding the mechanistic
causes of this disease is becoming increasingly critical. Recent clinical studies have linked increased stiffness
of the large arteries to both impaired memory and Alzheimer’s disease. It is hypothesized that these relations
are a result of large artery stiffness-induced cerebrovascular dysfunction. Increased large artery stiffness leads
to greater pulsatility of pressure and blood flow in the cerebral vasculature, which is known to cause vascular
damage. Dysfunction of the cerebral arteries and microvasculature is associated with cognitive impairment and
greater Alzheimer’s disease-related neuropathology. Furthermore, amyloid-β (Aβ) induces cerebrovascular
damage, and cerebrovascular impairment increases Aβ accumulation, thus creating a vicious cycle of
cerebrovascular dysfunction and neuropathology. The goal of the proposed studies is to provide the first proof-
of-concept evidence that age-related increases in large artery stiffness, synergistically with greater Aβ
production, lead to cognitive impairment, neuropathology, and cerebrovascular dysfunction. To accomplish this
goal, we will employ transgenic mouse models of greater large artery stiffness and greater Aβ production, as
well as use a pharmacological intervention to prevent age-related increases in large artery stiffness. In Aim 1,
we will assess the effects of large artery stiffness, in combination with Aβ, on cognitive dysfunction and
Alzheimer’s disease-related neuropathology. In Aim 2, we will determine the effect of large artery stiffness, in
combination with Aβ, on cerebral blood flow and cerebral vascular reactivity and structural integrity. In Aim 3,
we will identify candidate mechanisms by which large artery stiffness and greater cerebral artery pulsatility lead
to cerebrovascular dysfunction. To do so, we will examine the role and source(s) of vascular oxidative stress,
as well as perform transcriptome analysis of cerebral arteries and microvascular endothelial cells. The
knowledge to be gained by completing the proposed aims will inform future studies to identify novel therapeutic
targets for the prevention or attenuation of late-onset Alzheimer’s disease.
Terms: <AD dementia><Abeta synthesis><Advanced Glycation End Products><Advanced Glycosylation End Products><Affect><Aging><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimers Dementia><Amentia><Amyloid A4 Protein Precursor><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid Protein Precursor><Amyloid beta-Protein><Amyloid beta-Protein Precursor><Amyloid β><Amyloid β production><Amyloid β synthesis><Amyloid β-Peptide><Amyloid β-Protein><Amyloid β-Protein Precursor><Aorta><Area><Arteries><Attenuated><Aβ><Aβ production><Aβ synthesis><BBB permeabilization><BBB permeable><Bleeding><Blood Pressure><Blood Vessels><Blood capillaries><Blood flow><Body Tissues><Brain><Brain Nervous System><Brain Vascular><Brain Vascular Disorders><Brain Vascular reactivity><Carotid Arteries><Cerebrovascular Circulation><Cerebrovascular Disease><Cerebrovascular Disorders><Cerebrovascular system><Clinical Research><Clinical Study><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Collecting Cell><Data><Dementia><Development><Disease><Disorder><Disturbance in cognition><Dysfunction><Elastin><Elderly><Encephalon><Functional disorder><Future><Gene Expression><Genetic Alteration><Genetic Change><Genetic defect><Goals><Hemorrhage><Impaired cognition><Impairment><Intervention><Intervention Strategies><Intracranial Vascular Diseases><Intracranial Vascular Disorders><Knowledge><Late Onset Alzheimer Disease><Lead><Leanness><Learning><Link><Measures><Memory><Memory Deficit><Memory impairment><Methods><Mice><Mice Mammals><Modeling><Murine><Mus><Mutation><Nerve Cells><Nerve Degeneration><Nerve Unit><Neural Cell><Neurocyte><Neuron Degeneration><Neurons><Oxidative Stress><PSEN1><Pathology><Pb element><Phenotype><Physiopathology><Prevalence><Prevention><Primary Senile Degenerative Dementia><Pulse Pressure><Pyridoxamine><RNA Seq><RNA sequencing><RNAseq><Research><Risk><Risk Factors><Role><S182 protein><Source><Testing><Therapeutic><Thinness><Time><Tissues><Transgenic Mice><Vascular Diseases><Vascular Disorder><Vascular Endothelial Cell><Wild Type Mouse><a beta peptide><abeta><abeta accumulation><abeta aggregation><abeta production><advanced age><advanced glycation endproduct><advanced glycosylation endproduct><age associated><age correlated><age dependent><age linked><age related><age specific><aged brain><aged mice><aged mouse><aging brain><amyloid beta><amyloid beta accumulation><amyloid beta aggregation><amyloid beta production><amyloid beta synthesis><amyloid precursor protein><amyloid β accumulation><amyloid β aggregation><amyloid-b protein><arterial stiffening><arterial stiffness><arteriole><artery stiffening><artery stiffness><attenuate><attenuates><attenuation><aβ accumulation><aβ aggregation><beta amyloid fibril><blood flow in brain><blood loss><blood vessel disorder><blood vessels in the brain><blood-brain barrier permeabilization><blood-brain barrier permeable><bloodbrain barrier permeabilization><bloodbrain barrier permeable><brain blood circulation><brain blood flow><brain blood vessels><brain vascular disease><brain vascular dysfunction><brain vasculature><candidate identification><capillary><cerebral artery><cerebral blood flow><cerebral blood vessel><cerebral circulation><cerebral microbleeds><cerebral microhemorrhage><cerebral vascular><cerebral vascular disease><cerebral vascular dysfunction><cerebral vascular reactivity><cerebral vasculature><cerebro-vascular><cerebrocirculation><cerebrovascular><cerebrovascular blood flow><cerebrovascular dysfunction><cerebrovascular reactivity><cerebrovascular vessels><cerebrovasculature><cognitive dysfunction><cognitive loss><developmental><elderly mice><endothelial dysfunction><genome mutation><geriatric><global gene expression><global transcription profile><heavy metal Pb><heavy metal lead><human subject><inhibitor><innovate><innovation><innovative><interventional strategy><intracranial vascular dysfunction><late onset alzheimer><memory dysfunction><mouse model><murine model><neural degeneration><neural inflammation><neurodegeneration><neurodegenerative><neuroinflammation><neuroinflammatory><neurological degeneration><neuronal><neuronal degeneration><neuropathologic><neuropathological><neuropathology><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><old mice><pathophysiology><pharmacologic><presenilin 1 protein><presenilin-1><pressure><prevent><preventing><primary degenerative dementia><senile dementia of the Alzheimer type><senior citizen><social role><soluble amyloid precursor protein><transcriptome><transcriptome sequencing><transcriptomic sequencing><vascular><vascular dysfunction><vasculopathy><wildtype mouse>