i) To search for the genetic causes of vascular cognitive impairment and dementia
50 million people worldwide are now suffering from dementia; however, the exact causes remain elusive. Vascular Cognitive Impairment and Dementia (VCID) due to cerebrovascular diseases and pathologies represents 20~40% of the dementia cases, and largely overlaps with AD in terms of pathologies and pathogenic factors. Recently, we have been working with two groups of genetic risk factors that are vascular residents but can either predispose individual to cerebrovascular diseases or strongly modify the course of AD and VCID, such as platelet-derived growth factor receptor beta (PDGFRß), LRP1 and PICALM. Although this is just the first peek through the looking glass, yet our finding has brought new insight into the genetic causes of VCID and AD, suggesting that a better understanding the etiology and pathogenesis of AD and VICD, especially decoding the common genetic causes may help us redefining a subset of cases, and land more effective therapeutics for them in the near future.
ii) To study the molecular mechanism of the receptor-mediated transport at the blood-brain barrier
Receptor-mediated transcytosis (RMT) provides a major clearance pathway for Aß at the BBB, by flushing Aß out from brain to circulation. However, the understanding of this unique system remains limited, particularly regarding the molecular machinery which drives the cargos through multiple transcytosis events, including receptor-mediated endocytosis, intracellular trafficking, and exocytosis, as well as avoids the degradation pathway through late endosomes and lysosomes. Impaired vascular Aß clearance leads to elevated brain Aß level and exacerbates AD pathology. Piling evidence indicates that the alteration in the RMT system, particularly abnormal expression of AD vascular risk genes in the cerebral vasculature, contributes to pathogenesis. By studying the PICALM-dependent transvascular RMT machinery, we also hope to identify new key molecular targets of the BBB, which can be or manipulated pharmacologically or by adeno-associated virus (AAV)-mediated gene delivery, for more effective CNS drug delivery across the BBB.
iii) To examine the crosstalk between the cells within the neurovascular unit
Structural and functional brain connectivity, synaptic activity and information processing require highly coordinated signal transduction between different cell types within the neurovascular unit (NVU). The cells of the NVU are not just adjacently located and structurally connected; they communicated with each other vigorously via different signaling modules in order to function in orchestration. Such crosstalk is achieved by various cellular mechanisms, including but not limited to signaling receptors and channels, microRNA-containing exosomal vehicles (EVs) and gap junction-mediated direct exchange of small molecules. Neurovascular congruency is essential for the proper patterning of the CNS during development and neurovascular interaction is critical for normal brain functions, while its dysfunctions contribute to the pathogenesis of CNS injuries and neurodegenerative diseases, such as stroke and Alzheimer’s disease. We expect to provide evidence of functional pericyte–neuron crosstalk for brain health and functions, as well as pericyte contribution to brain’s innate immunity during CNS diseases or viral infections.