Combination therapy for vascular regeneration in a model of sporadic AD
Sunnybrook Research Institute
In people, mid-life high blood pressure leads to brain vascular disease and late-life dementia even when blood pressure is normalized. Therefore we propose to examine the effect of mid-life high blood pressure on memory and activities of daily living in a model that is susceptible to Alzheimer’s disease in comparison to a model of normal aging. We will determine the effect of the high blood pressure on the blood vessels within the brain, as they are responsible for delivering oxygen and nutrients to maintain a healthy brain. The objective of our study, after early normalization of blood pressure, is to directly target the brain’s vascular network. The use of specialized stem cells, which migrate to sites of injury including the brain, supply physiologically relevant support to the blood vessels and integrate directly into the blood vessel for structural support, is key to restoration of blood vessels to increase blood flow, oxygen and nutrient delivery to the brain, and thus lead to a healthier brain. We will examine the blood vessel structure and function within the brain using live imaging techniques, which are also used in people, and determine effects on perception, thinking, reasoning and remembering in our models.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
Covert strokes and small vessel disease are often visible with neuroimaging techniques and thus represent an approachable target. Our strategy for strengthening the structural and functional capacity of blood vessels, using cell transplantation and removal of Abeta, targets key components of neurovascular unit and complements treatments currently in clinical trials for AD. The correlation of magnetic resonance imaging changes to pathological outcomes will provide a preclinical map to guide scans in future patient studies. To facilitate clinical translation, scaled-up production in bioreactors will proceed via the established collaborations with CReATe Cord Blood Bank, a Canadian company.
At the end of this study, we expect to model more faithfully patients’ medical history. Our slow induction of hypertension and restoration to normotension in early prodromal phase of the AD-like phenotype and subsequent therapeutic intervention during early phases of the AD-like phenotype recapitulates the temporal evolution of sporadic AD patients with vascular comorbidity. Secondly, brain vascular repair will be effected, for the first time, via human umbilical cord perivascular cells, and thus we will determine the proof-of-concept for this therapeutic strategy. Lastly, combined in vivo imaging will provide us with sensitive and specific measures of changes in cerebrovascular structure and function in response to therapeutic interventions.
Final project summary
Our results demonstrate that normal F344 rats and our transgenic rat model of Alzheimer’s disease, F344 TgAD, are not different in their resting cerebral blood flow or in the response to an increase in demand for blood flow at 4 months of age, which represents the start of our study. We show that hypertension causes both normal and AD rats to exhibit a decreased resting blood flow and an increase in response to a mild carbon dioxide challenge; the latter is a method to investigate changes in cerebral blood flow that are required in times of increased demand such as during memory acquisition. These data demonstrate that hypertension has deleterious effects on brain blood flow that are greater in the AD rats than the normal rats. We went on to show that at this young age and after a 60-day recovery period the normal rats showed spontaneous recovery. In contrast, AD rats that had comorbid transient hypertension and early stage of AD pathology had a resting blood flow that was indistinguishable from the hypertensive state alone with an increase in hyperexcitability response to challenge demonstrating an interaction of hypertension with AD pathology. These data are similar to that seen in patients with mild cognitive impairment. We showed that stem cell treatment in combination with an A lowering drug restores both resting and demand blood flow levels to a greater extent than either treatment alone, thus proving our hypothesis.