The first Monday of each month, the Knight Initiative for Brain Resilience will host monthly seminars to bring together awardees, affiliated professors and students for a series of 'lab meeting' styled talks. Two speakers will discuss their brain resilience research, experiences in the field, and answer questions about their work.
To support our researchers' participation in this open science ‘lab-meeting style’ exchange of ideas, these seminars are not streamed/recorded and are only open to members of the Stanford community.
Kristy Zera, Stanford University
Blocking the VLA4/VCAM1 axis prevents infarct-induced neurodegeneration by reducing neuroinflammation and promoting vascular integrity
Infarct-induced neurodegeneration is a key factor in the high risk of post-stroke dementia, and a critical unmet therapeutic need. Here we blocked the VLA4/VCAM1 interaction during the weeks after stroke to elucidate its role in infarct-induced neurodegeneration. Vascular cell adhesion molecule 1 (VCAM1) facilitates immune cell diapedesis by binding very late antigen 4 (VLA4) on immune cells. We demonstrate that blocking antibodies against either VCAM1 or VLA4 prevent delayed cognitive impairment after stroke when mice are treated chronically beginning 4 days after stroke. Stroked mice treated with isotope control antibody developed a cognitive deficit in both Barnes maze and novel object by 6 weeks, while anti-VCAM1 and anti-VLA4 treated mice performed comparably to sham animals on both tasks. Using high-depth single-cell RNA sequencing we demonstrate that transcriptional effects on endothelial cells are much stronger than on immune cells and that both antibodies increase expression of blood vessel growth and maturation genes. Additionally, blocking VCAM1 but not VLA4 decreases immune cell infiltration, but both increase pericyte vascular coverage, and reduce extravascular fibrinogen leakage. Together, our findings indicate that blocking the VLA4/VCAM1 axis is a promising target to preserve vascular integrity and to prevent infarct-induced neurodegeneration.
Carla Shatz, Stanford University
Convergence of signals for pruning at a synaptic receptor implicated in Alzheimer's disease
Memories are stored at synapses and circuits, which tragically are pruned and deconstructed in Alzheimer's disease (AD). Genetic mutations including APP generate high levels of soluble oligomeric beta amyloid (oAbeta42), leading to insoluble beta amyloid plaques - hallmarks of late-stage disease. Clinical trials have designed "plaque-busting" drugs assuming that plaques cause disease. However, disappointing outcomes demand new approaches. Inflammation is also an AD risk factor, including complement cascade molecules. We have discovered that complement C4 cleavage generates a fragment that binds with high affinity to human LilrB2/mouse PirB, a receptor in brain needed for pruning. Human genetic studies identify LilrB2 as a significant AD risk locus. PirB/LilrB2 is also a known receptor for oAbeta42. Here we propose that PirB/LilrB2 receptor is a convergence point for binding both oAbeta42 and C4 fragment, and that these 3 molecules are located at synapses to drive excessive synapse loss. Our work implies that treatments targeting just amyloid plaques not only happen too late but also do not recognize the possibility that even if oAbeta is targeted, a known pruning receptor for complement remains: the receptor should be targeted. This research can illuminate new ways of thinking about AD mechanisms, leading to new therapeutic approaches.