From the Department of Neurology (P.W.T., G.S.D., O.P.F., N.E.-T., N.G.-R.), Department of Neuroscience (M.A., A.I.S.-B., Z.S.Q., J.S.R., N.E.-T., O.R.), Department of Neurosurgery (S.S.G., K.C.), Division of Clinical Trials and Biostatistics (C.T.B., M.G.
Citations 2
CWH43
Variants Are Associated With Disease Risk and Clinical Phenotypic Measures in Patients With Normal Pressure Hydrocephalus
Neurology Genetics | July 19, 2023 | Volume: 9 | Issue: 5 | Pages: No page available
There is considerable interest in harnessing innate immunity to treat Alzheimer’s disease (AD). Here, we explore whether a decoy receptor strategy using the ectodomain of select TLRs has therapeutic potential in AD. AAV-mediated expression of human TLR5 ectodomain (sTLR5) alone or fused to human IgG4 Fc (sTLR5Fc) results in robust attenuation of amyloid β (Aβ) accumulation in a mouse model of Alzheimer-type Aβ pathology. sTLR5Fc binds to oligomeric and fibrillar Aβ with high affinity, forms complexes with Aβ, and blocks Aβ toxicity. Oligomeric and fibrillar Aβ modulates flagellin-mediated activation of human TLR5 but does not, by itself, activate TLR5 signaling. Genetic analysis shows that rare protein coding variants in human TLR5 may be associated with a reduced risk of AD. Further, transcriptome analysis shows altered TLR gene expression in human AD. Collectively, our data suggest that TLR5 decoy receptor–based biologics represent a novel and safe Aβ-selective class of biotherapy in AD.