Amyloid-β-Derived Peptidomimetics Inhibits Tau Aggregation

Abstract

The aggregation of tau protein is one of the hallmarks for Alzheimer’s disease, resulting in neurodegeneration. The peptidomimetics strategy to prevent tau aggregation is more specific over other small molecules. In the present study, we analyzed the effect of amyloid-β-derived peptidomimetics for inhibiting heparin-induced tau aggregation in vitro . These peptides and their derivatives were known to prevent aggregation of amyloid-β. KLVFF is a hydrophobic sequence of the pentapeptide that prevented tau aggregation as observed by thioflavin S fluorescence, transmission electron microscopy, and circular dichroism spectroscopy. P4 and P5 also prevented assembly of tau into aggregates and formed short fibrils. The β-sheet breaker LPFFD was however ineffective in preventing tau aggregation. The peptides further demonstrated reversal of tau-induced cytotoxicity in a dose-dependent manner. Our results suggested that these peptides can also be used to inhibit tau aggregation and also, toxicity induced by tau could be considered as potential molecules that have an effect on tau as well as amyloid-β.

Multipronged diagnostic and therapeutic strategies for Alzheimer's disease

“…The treatment of a Tg mouse model with mAb Ta1505 developed against pSer413 has reduced tau burden and improved synaptic density and cognitive decits. 191 Preclinical evaluation of two mAbs 43D (against tau 6-18) and 77 × 10 9 (against tau [184][185][186][187][188][189][190][191][192][193][194][195] revealed a reduction of tau burden and rescued from cognitive decits. 192 Six doses of 43D mAb effectively reduced total tau, hyperphosphorylated tau and rescued the 3xTg mouse model from spatial and short-term memory.…”

“…230 Hybrid peptoids P4 and P5 modulate both Aβ and tau aggregation. 143,184 These peptoids effectively rescue neuronal cells from Aβ and tau toxicity. Recently, we have screened a focused library of 52 thiophene-based small molecules targeting Aβ aggregation and identified five lead candidates.…”

Aβ and Tau Interact with Metal Ions, Lipid Membranes and Peptide-Based Amyloid Inhibitors: Are These Common Features Relevant in Alzheimer’s Disease?

“…It would be of interest to explore whether the above described peptides, known to prevent aggregation of amyloid-β, would exhibit a promising dual role in preventing amyloidβ as well as tau aggregation, as demonstrated by Gorantla et al who screened LPFFD, KLVFF, and related derivatives containing thymine and sarcosine units (Table 1) [168].…”

Clinical relevance of biomarkers, new therapeutic approaches, and role of post-translational modifications in the pathogenesis of Alzheimer’s disease

“…Interestingly, the amyloid-β-derived peptides prevented in vitro tau aggregation and their inhibitory effect on tau and non-toxic nature points to their therapeutic importance in overcoming AD ( Hampel et al, 2015 ; Kametani and Hasegawa, 2018 ; Abeysinghe et al, 2020 ; Farheen et al, 2021 ). Nanomaterials help in hindering amyloid protein growth and its accumulation due to their highly sensitive molecular detection and identification ( Elbassal et al, 2017 ; Li et al, 2019 ; Jara-Guajardo et al, 2020 ; Gorantla et al, 2021 ). Due to their ability to cross BBB, nanomaterials have been used to identify AD biomarkers, and to study the beta-amyloid protein and tau proteins pathological mechanism ( Kametani and Hasegawa, 2018 ).…”