TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer’s disease

Abstract

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.

Tumor Necrosis Factor (TNF) blocking agents are associated with lower risk for Alzheimer’s disease in patients with rheumatoid arthritis and psoriasis

“…Alzheimer's brain and soluble fragments have been shown to act as decoy receptors to ameliorate disease phenotypes in a transgenic mouse model of AD [46]. NFKBIA and NFKBIZ are components of the nuclear I kappa B protein signaling pathway that regulates the expression of TNF while TNFSR1A encodes the TNF receptor superfamily member 1A that is activated by TNF [47].…”

ADSoluble aggregates present in cerebrospinal fluid change in size and mechanism of toxicity during Alzheimer’s disease progression

“…Taken together, these results indicate that a combination of therapeutic agents targeting aggregated species with varying size and morphology, rather than a single agent targeting a single structure of one toxic form of Aβ may be needed to develop effective treatments for AD. 9…”

“…(i) permeabilisation of cell membranes by non-specific binding 7,8 and (ii) specific interactions with receptors in cell membranes 6,9 . It is also known that the morphology of protein aggregates can determine the level of their involvement in different biological interactions.…”

“…It is also known that the morphology of protein aggregates can determine the level of their involvement in different biological interactions. Hydrophobic protein aggregates more readily interact with hydrophobic lipid membranes, while the size and shape of the aggregates determine the affinity of binding to receptors 6,[8][9][10] . Understanding how the intrinsic heterogeneity in the size, shape and structure of the aggregates present in the human brain influences their mechanism of toxicity and how such heterogeneity changes as AD progresses is crucial in identifying the molecular pathways that lead to neuronal death.…”

Alzheimer’s Disease Neuroprotection: Associated Receptors

“…In turn, APP fibrils modulate the human TLR5 activation via flagellin, but APP cannot activate TLR5 signaling by themselves. Thus, TLR5-related biological data suggest this receptor as a potential agent in AD therapy [30]. A new TLR9 signaling pathway has recently been associated with the immune-inflammatory response, reducing Aβ levels in AD mice.…”