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  • Two excellent GSMs with clear pharmacological

    2021-09-26

    Two excellent GSMs with clear pharmacological effect across rats, dogs, monkeys, and human subjects are BMS-932481 and BMS-986133 with IC50 at 6.6 and 3.5 nM to reduce Aβ42, respectively. Both GSMs exhibit dose- and time-dependent activity in vivo by decreasing Aβ1-42 and Aβ1-40 levels while increasing Aβ1-38 and Aβ1-37 [130,131]. Although the mechanism and central activity of these GSMs translate across preclinical species and humans, insufficient margin for human safety prevents further testing for efficacy of Aβ lowering in AD patients [131]. A unique GSM, BPN-15606, exhibited an IC50 of 7 nM and 17 nM to reduce Aβ42 and Aβ40 from cultured cells, with a concomitant increase of Aβ38 and no change in total Aβ [132]. BPN-15606 binds to an allosteric site within the γ-secretase complex and does not affect Notch cleavage at 25 μM. Dose dependent decreases of plasma, kobe2602 receptor and CSF Aβ were found in both mice and rats. Chronic dosing of transgenic mice with BPN-15606 significantly reduced accumulation of Aβ plaques in both the hippocampus and cortex. Like previous reported BACE inhibitors [133], BPN-15606 treatment of 3-dimensional neuronal culture decreased total tau and phosphorylated pThr181 tau [132]. Based on in vivo pharmacokinetic profile of BPN-15606, sub micromolar plasma exposures of BPN-15606 expect to achieve a significant lowering of Aβ42 in human brain, thus requiring much lower doses than those reported for BMS-932481 and BMS-986133.
    Detecting efficacy of γ-secretase modulators: in 20 years? It is widely accepted that future AD therapies need to start at an earlier stage, as the onset of disease may occur 15–20 years before the appearance of clinical symptoms [134]. One of major factors contributing to the failure of GSIs and GSMs could be the timing of treatment, i.e., patients at mild to moderate stage might be too late for Aβ reducing therapies as neuronal damage is extensive and irreversible. To test asymptomatic patients at very early stages of disease, biomarkers are needed to identify those subjects for clinical trials. Alternative approaches have been pursued in AD patients carrying FAD mutations (e.g., Dominantly Inherited Alzheimer’s Network). The Alzheimer’s Prevention Initiative (API) was created for clinical trials of Aβ vaccine in pre-symptomatic members from an extended Colombian family carrying a PS1 mutation. Specific GSMs reversing familial mutant PS1/γ-secretase activity may be ideally positioned for those subjects [135]. Anti-Amyloid Treatment in Asymptomatic AD Trial (A4) with brain amyloid imaging has enrolled over a thousand asymptomatic subjects. Therapeutic development with brain imaging and cognitive function as efficacy readouts has been pursued [136], and new Aβ-reducing approaches might be effective in patients with MCI and in pre-symptomatic AD patients. With recent development of GSMs such as BPN-15606 [132] or endogenous cholesterol metabolite cholestenoic acid [137], it does not take 20 years to wait for AD patients converting from pre-symptomatic to symptomatic stages while testing efficacy of GSMs. Advancements in brain imaging and fluid biomarkers will greatly facilitate the discovery of disease modifying therapeutics for AD.
    Acknowledgements
    Introduction Alzheimer's disease (AD) is a destructive neurodegenerative disorder and the most common cause of dementia in the aged people. Extracellular localized amyloid senile plaques and intracellular neurofibrillary tangles (NFTs) are the neuropathological hallmarks of AD. While the senile plaques are composed of amyloid-β protein (Aβ), the NFTs are mainly built up of hyperphosphorylated forms of the microtubule-associated protein tau [1,2]. γ-Secretase complex, composed of Nicastrin (NCT), presenilin (PS), anterior pharynx defective1 (Aph-1) and presenilin enhancer-2 (PEN-2), is responsible for the cleavage of amyloid precursor protein (APP) to generate Aβ [[3], [4], [5], [6], [7]]. Posttranslational protein modification such as glycosylation is greatly involved in various diseases by modulating subcellular localization, enzymatic activity and protein-protein interaction of the key disease related glycoproteins. For example, failure to produce mannose 6-phosphate modification on N glycan in the Golgi, a signal for trafficking of hydrolases to lysosomes, resulting in storage disorder like I-Cell disease also known as mucolipidosis II. Defects in endocytosis and trafficking of glycosidases to lysosomes also causing cellular storage disorders such as Gaucher's, Niemann-Pick Type C, Sandoff's, and Tay Sacks diseases [8]. Since several studies have suggested that most AD related proteins such as APP, BACE1, γ-secretase subunit NCT and α-secretase ADAM10 are decorated with glycans and protein glycosylation is altered in AD, the development and progression of AD most likely regulated by glycosylation although the precise roles of glycans in AD remains largely unknown [9,10]. NCT is a type I integral membrane protein and plays important role in γ-secretase activity by interacting with the catalytic subunit presenilin (PSEN1/2). Among the γ-subunits, NCT is the only subunit that is N-glycosylated and has 16 potential N-glycosylation sites [11,12].