A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models

Abstract

Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer’s disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy. Here we describe a high-affinity human TREM2-activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), to facilitate blood–brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared to a standard anti-TREM2 antibody. In human induced pluripotent stem cell (iPSC)-derived microglia, ATV:TREM2 induced proliferation and improved mitochondrial metabolism. Single-cell RNA sequencing and morphometry revealed that ATV:TREM2 shifted microglia to metabolically responsive states, which were distinct from those induced by amyloid pathology. In an AD mouse model, ATV:TREM2 boosted brain microglial activity and glucose metabolism. Thus, ATV:TREM2 represents a promising approach to improve microglial function and treat brain hypometabolism found in patients with AD.

Exploring Options for Proximity-Dependent Biotinylation Experiments: Comparative Analysis of Labeling Enzymes and Affinity Purification Resins

“…From this information, it is difficult to predict amounts of resin with exactly equivalent binding capacities, given the different sizes of biotinylated standards (BSA: 66 kDa; IgG: 150 kDa), the likely different numbers of biotinylated residues, and only a minimum estimate of binding capacity for MagReSyn MS resin. Nonetheless, a wide range of sample-to-resin ratios have been utilized with other formulations of these magnetic resins, − so we tested three different volumes of MagReSyn MS slurry (10, 20, and 40 μL, hereafter designated “M10”, “M20”, and “M40”, respectively). In parallel, we purified proteins on 10 μL of a sepharose resin slurry (“S10”), which we have found to perform satisfactorily with reduced lysate inputs (100 μL of lysate brought to a total volume of 300 μL in lysis buffer, representing (2–3) × 10 6 HEK293 Flp-In T-REx cells and approximately 600 μg of total protein in the cleared lysate fraction) (data not shown).…”

Intrathecal Pseudodelivery of Drugs in the Therapy of Neurodegenerative Diseases: Rationale, Basis and Potential Applications

“…Lastly, a TREM2-activating antibody with a BBB transport vehicle enhances microglial metabolism in AD models [ 89 ] and tau pathology and neurodegeneration are associated with an increase in CSF sTREM2 [ 90 ]. However, some of these experiments can be interpreted as full-length TREM2 protecting rather than sTREM2 [ 26 ].…”

Jedi-1/MEGF12-mediated phagocytosis controls the pro-neurogenic properties of microglia in the ventricular-subventricular zone

“…Beyond more deeply understanding the signaling events that follow Jedi activation in neonatal microglia, the extent to which changes in Jedi expression correlate with the response to or onset and progression of neuropathology in the adult and aging brain should be explored. Pharmacological targeting of engulfment receptors is gaining significant attention in pre-clinical and clinical research 67,68 , and it may prove beneficial, as it has for TREM2 [69][70][71] , to explore Jedi in these spheres.…”