Discovery

Washington University wins NIA grant to study immune clearance in Alzheimer's disease

Note: The orglookupsummary returned a mismatched result (Western Washington University) that does not correspond to the funded institution, Washington...

Edited by Robert McTiernan··3 min read
Washington University wins NIA grant to study immune clearance in Alzheimer's disease

Washington University in St. Louis has received a USD 3.06 million National Institute on Aging renewal award to investigate how innate immune cells and the brain's lymphatic drainage system interact to drive — or potentially limit — Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). The P01 program project grant, now in its fifth year, funds a multidisciplinary team targeting clearance mechanisms that have received comparatively little attention from the AD field.

The program is led by Jonathan Kipnis, whose laboratory has been central to establishing the meningeal lymphatic system as a functional component of brain waste clearance. The grant supports four interlocking projects led by Kipnis, David Holtzman, Gwendalyn Randolph, and Marco Colonna — all based at Washington University — alongside imaging and surgical cores.

Most prior AD research has concentrated on parenchymal microglia and amyloid-beta plaque burden in brain tissue. This program redirects attention toward parenchymal border macrophages (PBMs) — perivascular and leptomeningeal cells that line the brain's borders — and their relationship with meningeal lymphatic drainage of cerebrospinal fluid (CSF).

The central hypothesis, as the investigators describe it, is that dysfunction in this neuroimmune axis — spanning PBMs, microglia, and the meningeal lymphatic network — underlies both AD and CAA pathology. CAA, in which amyloid deposits accumulate in cerebral vessel walls rather than brain parenchyma, contributes to vascular dysfunction and is present in a substantial proportion of AD patients, yet has been underrepresented in mechanistic studies.

The four projects examine complementary aspects of the pathway, spanning PBM biology (Kipnis), ApoE and meningeal lymphatics in CAA (Holtzman), interactions between lymphatics, HDL and border macrophages (Randolph), and Syk-mediated innate immune signaling (Colonna).

The convergence on cholesterol metabolism, ApoE, and downstream TREM2 (triggering receptor expressed on myeloid cells 2) signaling reflects the field's growing recognition that lipid homeostasis in myeloid cells is a central regulator of microglial and macrophage function in neurodegeneration.

The AllSci BriefSystematic R&D and deal news. Daily.

The team reports using newly developed intravital imaging approaches, in vivo microanalysis, novel transgenic mouse lines, and unique surgical techniques to interrogate these pathways in preclinical models. The imaging and surgery core, led by Randolph, supports all four projects.

This is exclusively preclinical, mechanistic research. No clinical translation is described in the current award period, which runs through May 2027.

Competitive and funding context

The meningeal lymphatic field has attracted substantial preclinical interest since Kipnis and colleagues described functional lymphatic vessels in the mouse meninges in 2015. Subsequent work from multiple groups has linked lymphatic dysfunction to amyloid accumulation and cognitive decline in mouse models, and several companies — including those developing VEGF-C-based approaches to augment lymphatic function — have begun exploring therapeutic angles.

On the innate immunity side, TREM2-targeting strategies have been pursued by several industry players, led by programs from Alector and, more recently, Sanofi through its acquisition of Vigil Neuroscience. Although these agents have demonstrated target engagement, clinical efficacy has yet to be convincingly established. The Syk kinase axis targeted in Colonna's project represents a less clinically advanced but mechanistically distinct entry point into myeloid cell modulation in AD.

Access the AllSci platform to explore the science behind the news.

Spot something wrong? Report an issue with this article