A brain-penetrant triazolopyrimidine enhances microtubule-stability, reduces axonal dysfunction and decreases tau pathology in a mouse tauopathy model

Abstract

BackgroundAlzheimer’s disease (AD) and related tauopathies are neurodegenerative diseases that are characterized by the presence of insoluble inclusions of the protein tau within brain neurons and often glia. Tau is normally found associated with axonal microtubules (MTs) in the brain, and in tauopathies this MT binding is diminished due to tau hyperphosphorylation. As MTs play a critical role in the movement of cellular constituents within neurons via axonal transport, it is likely that the dissociation of tau from MTs alters MT structure and axonal transport, and there is evidence of this in tauopathy mouse models as well as in AD brain. We previously demonstrated that different natural products which stabilize MTs by interacting with β-tubulin at the taxane binding site provide significant benefit in transgenic mouse models of tauopathy. More recently, we have reported on a series of MT-stabilizing triazolopyrimidines (TPDs), which interact with β-tubulin at the vinblastine binding site, that exhibit favorable properties including brain penetration and oral bioavailability. Here, we have examined a prototype TPD example, CNDR-51657, in a secondary prevention study utilizing aged tau transgenic mice.Methods9-Month old female PS19 mice with a low amount of existing tau pathology received twice-weekly administration of vehicle, or 3 or 10 mg/kg of CNDR-51657, for 3 months. Mice were examined in the Barnes maze at the end of the dosing period, and brain tissue and optic nerves were examined immunohistochemically or biochemically for changes in MT density, axonal dystrophy, and tau pathology. Mice were also assessed for changes in organ weights and blood cell numbers.ResultsCNDR-51657 caused a significant amelioration of the MT deficit and axonal dystrophy observed in vehicle-treated aged PS19 mice. Moreover, PS19 mice receiving CNDR-51657 had significantly lower tau pathology, with a trend toward improved Barnes maze performance. Importantly, no adverse effects were observed in the compound-treated mice, including no change in white blood cell counts as is often observed in cancer patients receiving high doses of MT-stabilizing drugs.ConclusionsA brain-penetrant MT-stabilizing TPD can safely correct MT and axonal deficits in an established mouse model of tauopathy, resulting in reduced tau pathology.Electronic supplementary materialThe online version of this article (10.1186/s13024-018-0291-3) contains supplementary material, which is available to authorized users.

Correction of microtubule defects within Aβ plaque‐associated dystrophic axons results in lowered Aβ release and plaque deposition

“…The study results further emphasize that MT abnormalities appear to be a key feature of AD, as well as other neurodegenerative diseases 31 . Importantly, small molecule MT‐stabilizing agents such as 51657 can reduce AD‐like pathology and confer neuronal benefits in mouse models with only tau pathology 21,22,28,36,39 or in mice with only Aβ pathology, as demonstrated here. MT‐stabilizing compounds are thus unique in being able to independently affect the two key pathologies found in the AD brain.…”

“…Moreover, these low doses of epothilone D did not lead to changes in blood cell counts, including neutrophils, 28 which is a leading side effect when MT‐stabilizing drugs are used in oncology settings 44,45 . Similarly, the doses of 51657 that led to improvements in tau Tg mice, and here in Tg Aβ plaque mice, did not affect neutrophil or other blood cell counts 39 . Finally, the doses of epothilone D used in the short Phase 1b trial, which were similar to those used in Tg mouse studies when scaled for species, did not result in adverse events 43 .…”

“…Importantly, these molecules increased MT density and normalized MT dynamics, with a corresponding improvement of axonal transport and reduction in tau pathology, synapse loss, and neuronal death. More recently, a non‐natural product compound referred to as CNDR‐51657 (hereafter 51657), 37 which stabilizes MTs by binding to a different site than the aforementioned natural products, 38 conferred similar benefits in tau Tg mice 39 . As senile plaque‐associated dystrophic axons have also been shown to have MT abnormalities, 32,34 we hypothesized that normalization of MT structure/function in these swollen processes with a previously characterized MT‐stabilizing compound might improve regional axonal transport and slow the focal accumulation of cellular proteins such as APP and BACE1, thereby reducing Aβ generation.…”

Metformin treatment improves the spatial memory of aged mice in an APOE genotype–dependent manner

“…Unfortunately, the current study found that metformin contributed to increased phospho-tau in both ApoE3-TR mice and ApoE4-TR mice. Previous studies reported that metformin decreases phospho-tau or promotes its aggregation in young or tauopathy mice (56,57). The inconsistency may be due to the fact that the current study probed into phospho-tau in old ApoE-TR mice under a chronic metformin treatment.…”

“…Hyperphosphorylated tau plays an important role in the formation of neurofibrillary tangles in brains of AD patients and related tauopathies (56,57). Several studies suggest that ApoE4 increases the levels of phospho-tau (34)(35)(36).…”