Mysterious factors in the blood are known to trigger aging in the brain. Though researchers have yet to discover the identities of all these aging agents, they have pegged a protein that lets them do their dirty work. On May 13 in Nature Medicine, researchers led by Tony Wyss-Coray at Stanford University in Palo Alto, California, reported that vascular adhesion molecule 1 (VCAM1) expression on the endothelial cells that line the blood-brain barrier is required for systemic factors to accelerate aging in the mouse brain. Blocking VCAM1 not only countered classic signs of brain aging such as microglial activation and waning neurogenesis, it also bestowed old mice with the memory of murine whippersnappers.
- VCAM1 expression on brain endothelial cells was required for aged plasma to accelerate aging of the brain in mice.
- VCAM1 also facilitated normal brain aging in untreated mice.
- Blocking VCAM1 with antibodies slowed brain aging.
Alzforum covered much of this work when Wyss-Coray spoke at Keystone, and based on a manuscript on bioRχiv (Jul 2018 conference news). The freshly published work adds behavioral studies.
VCAM1 is part of the immunoglobulin receptor family, and its expression rises on many cell types in response to injury. The receptor binds to the integrin VLA4 on leukocytes. VCAM1 is also continually shed from the membrane by ADAM17 protease, resulting in a soluble pool of the protein. As presented at Keystone, VCAM1 expression by a subset of brain endothelial cells (BECs) shot up with age in mice, and infusing young animals with plasma from old mice or humans revved up its expression, as well.
Wyss-Coray had previously reported that plasma from old mice triggered microglial activation and slowed neurogenesis in young mice, while blood from young mice countered these effects in older animals (Nov 2009 conference news; Aug 2011 news). Blocking VCAM1 with an antibody, or nixing its expression in BECs, countered old plasma’s aging effects. The treatment even calmed microglia and maintained neurogenesis in mice aged the old-fashioned way, without plasma infusions.
VCAM1 Opens Door to Aging. In young mice, low VCAM1 on BECs allows microglia to remain ramified and calm, and neurogenesis to proceed. In the old brain, BECs ramp up VCAM1 expression, which tethers more leukocytes to their luminal side. This activates microglia and suppresses neurogenesis. Anti-VCAM1 antibodies block the effects of aged plasma and rejuvenate the brain (bottom). [Courtesy of Yousef et al., Nature Medicine, 2019.]
In their published paper, first author Hanadie Yousef and colleagues now added results of a battery of memory tests. Old mice took longer to learn the location of a hidden escape box than young mice, but oldsters learned as fast as young’ns when injected with an anti-VCAM1 antibody once every three days for a month. Similarly, 17-month-olds treated with anti-VCAM1 distinguished between new and familiar objects almost as well as young mice, while old mice dosed with a control antibody could not tell the difference. Blocking VCAM-1 improved fear-conditioning memory, i.e., freezing, in 23-month-old mice placed into a context in which they had previously received a foot shock.
The researchers also delivered the anti-VCAM1 antibody to 13-month-old NSG mice, which age fast, with rapid cognitive decline. Treated NSG mice outperformed controls on the novel object recognition, though not the fear conditioning test.
The authors proposed a scenario in which inflammatory proteins in the blood that rise with age—such as TNF-α and IL-1β—boost expression of VCAM1 on BECs, thus promoting tethering of leukocytes via VLA-4 binding. The leukocyte tethering inflames the endothelium, which signals into the brain parenchyma, activating microglia and stifling neurogenesis. The scientists proposed VCAM1 as a potential therapeutic target for age-related neurodegenerative diseases.—Jessica Shugart
- Yousef H, Czupalla CJ, Lee D, Chen MB, Burke AN, Zera KA, Zandstra J, Berber E, Lehallier B, Mathur V, Nair RV, Bonanno LN, Yang AC, Peterson T, Hadeiba H, Merkel T, Körbelin J, Schwaninger M, Buckwalter MS, Quake SR, Butcher EC, Wyss-Coray T. Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nat Med. 2019 Jun;25(6):988-1000. Epub 2019 May 13 PubMed.