The clinical manifestations resulting from AD include memory and cognitive impairment, anxiety, confusion, language difficulties, and mood swings. Current treatments including acetylcholine esterase inhibitors or NMDA receptors antagonists are somehow symptomatic, showing side-effects and may not heal the disease. Despite extensive considerations, an efficient therapeutic has remained elusive thus far.
AD is characterized by the deposition of β-amyloid (Aβ) protein oligomers and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein (P-tau), serving as the primary pathological signs of AD.
There have been various strategies to eliminate pathogenic amyloids. The most important antibody against neurotoxic amyloid is Adecunumab by Biogen, which showed disappointing results; especially at later stages of the disease.
Although β-amyloids are indeed neurotoxic, there are increasing evidence that tau abnormalities overlap better with AD development.
Tau hyperphosphorylation and aggregation is a long-lasting process; sometimes over years! Thus, this is of crucial importance to demonstrate which phosphorylation event triggers tau pathogenicity.
We have previously shown that phosphorylated tau at the Thr231-Pro232 motif in cis conformation is extremely neurotoxic and yields the loss of normal tau functions. However, we have recently found that neurotoxic pT231-tau conformer in human brain is different from rodents. We had a few shots in the dark to reach to the specific pT231-tau conformer, which is pathogenic in human neurons. We have generated a fully human monoclonal antibody (scFv domain) against the pathogenic conformer and have shown that antibody may recognize pathogenic pT231-tau species and suppress tau pathogenicity and neurodegeneration in AD human neurons (patent # US 10,570,195 B2).