A TREM2-activating antibody with a blood-brain barrier transport vehicle enhances microglial metabolism in Alzheimer's disease models.
Bettina van LengerichLihong ZhanDan XiaDarren ChanDavid A JoyJoshua I ParkDavid TatarakisMeredith CalvertSelina HummelSteve LianoglouMichelle E PizzoRachel ProrokElliot ThomsenLaura M BartosPhilipp BeumersAnja CapellSonnet S DavisLis de WeerdJason C DugasJoseph DuqueTimothy EarrKapil GadkarTina GieseAudrey GillJohannes GnörichConnie HaMalavika KannuswamyDo Jin KimSebastian T KunteLea Helena KunzeDiana LacKendra LechtenbergAmy Wing-Sze LeungChun-Chi LiangIsabel LopezPaul McQuadeAnuja ModiVanessa O TorresHoang N NguyenIda PesämaaNicholas PropsonMarvin ReichYaneth Robles-ColmenaresKai SchlepckowLuna SlemannHilda SolanoyJung H SuhRobert G ThorneChandler VieiraKarin Wind-MarkKen XiongY Joy Yu ZucheroDolo DiazMark S DennisFen HuangKimberly A Scearce-LevieRyan J WattsChristian HaassJoseph W LewcockGilbert Di PaoloMatthias BrendelPascal E SanchezKathryn M MonroePublished in: Nature neuroscience (2023)
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.
Keyphrases
- blood brain barrier
- cerebral ischemia
- single cell
- inflammatory response
- stem cells
- endothelial cells
- neuropathic pain
- mouse model
- signaling pathway
- white matter
- high glucose
- lipopolysaccharide induced
- resting state
- cognitive decline
- innate immune
- oxidative stress
- metabolic syndrome
- gene expression
- adipose tissue
- high throughput
- induced pluripotent stem cells
- spinal cord injury
- bone marrow
- type diabetes
- pluripotent stem cells
- mild cognitive impairment
- binding protein
- cell therapy
- cancer therapy
- drug induced
- insulin resistance