J147: the next step in disease-modifying therapy for Alzheimer’s?

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Highlights:

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• Alzheimer’s disease is a debilitating neurodegenerative condition
• Drug discovery strategies targeted at amyloid-β or tau protein showed limited success, with attention shifting towards a more comprehensive approach to drug screening
• J147 is a curcumin derivative with promising geroprotective properties
• Preclinical studies in mice showed that J147 improves physical and cognitive parameters while decreasing levels of AD-associated biomarkers 
• J147 presents a multitude of possibilities, both as a potential anti-AD drug and geroprotector

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Introduction

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Alzheimer’s disease (AD) is a neurodegenerative disease linked to a plethora of complex processes that lead to neural cell dysfunction and death. It has been marked as the sixth leading cause of death in the United States and the fifth leading cause among people over 65. Though the biology of AD is increasingly well understood, there are still no effective therapies for curing or modifying the disease that would be able to address cognitive impairment and neuropsychiatric syndromes accompanying the disease. Progress is, nevertheless, made with 143 drug candidates in 172 trials (as of 25 January 2022). In this article, we are going to focus on the particular drug candidate – J147, a curcumin derivative with a promising anti-AD profile and geroprotective properties. 

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In search of a drug candidate

The brain affected by AD is characterized by synaptic and neuronal loss accompanied by the formation of amyloid plaques and neurofibrillary tangles. Amyloid-β is a peptide that, when misfolded, creates aggregates toxic to neural cells (1). On the other hand, the formation of neurofibrillary tangles (which disrupt neuronal connectivity) is linked to the tau protein, whose primary function is to maintain cell shape and integrity (2).

Amyloid-β and tau protein are logically amongst the most popular targets during the initial screening phases (3–5). However, analysis of emerging therapeutics based on CADRO (Common Alzheimer’s Disease Research Ontology) categories shows that a few of the emerging therapeutics are focused either on amyloid reduction (~4% of drug candidates) or tau protein (another ~4% of drug candidates) (6). However, the drug development focused solely on amyloid plaques removal showed limited success, with a single drug – aducanumab – being approved by the Food and Drug Administration (7), and even its use remains problematic due to the connected brain abnormality risks and high price. The strategies focused on inhibition of tau kinases or tau aggregation mainly were discontinued due to accompanying toxicity and lack of efficacy (8). Currently, the key mechanisms targeted by the emerging AD therapeutics are inflammation, cell death, proteostasis (a process that supports the healthy functioning of the proteins in a cell), neuroprotection, and neurogenesis (6).

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Multimodal approach

Given all the abovementioned factors, the team led by Dave Schubert embarked on a search for new potential anti-AD agents. Instead of focusing on a single target, they developed a multimodal drug-screening approach mimicking the changes that occur in the aging brain (9), thus essentially searching for geroprotective compounds. The compounds were screened in four assays that assessed cell survival under low metabolism, oxidative stress, proteotoxicity (misfolded protein accumulation), and reduced cell-to-cell signaling. Additionally, anti-inflammatory activity was accessed in a separate assay.

Several promising compounds were discovered, including a compound later coded under the name J147. J147 is a derivative of curcumin and cyclohexyl-bisphenol A. Curcumin is well known for its potential anti-inflammatory properties but in pure form has low bioavailability and stability limiting its potential use. On the other hand, cyclohexyl-bisphenol A carries known neurotrophic properties (supports the growth and survival of neurons), which curcumin lacks.

Preclinical studies in SAMP8 mice (a special breed of mice that tend to develop brain changes similar to those of AD patients) demonstrated that J147 reduced cognitive deficits in older mice while simultaneously improving multiple biomarkers associated with human AD, vascular pathologies, and inflammation (10). The positive effects also included general improvement in physical and cognitive parameters, suggesting that J147 might be active by preventing specific metabolic changes associated with aging. In another murine study (11), the researchers demonstrated that J147 could reduce soluble amyloid levels, stimulate neural stem cell growth, enhance memory, and improve the density of synapses in old mice.

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The mechanism behind

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Despite the promising results, the mechanism behind the J147 action was not clear. In their subsequent study, the researchers employed several varying approaches to detect its molecular target. The search identified a J147’s target as an ATP5A protein – a subunit of a mitochondrial protein called ATP synthase (12). The main function of this protein within a cell is to participate in ATP (adenosine triphosphate) generation. 

It is well known that mitochondria regulate various metabolic signaling pathways and participate in programs of cell survival and death. The identification of this target suggests that aging and dementia are closely related on a molecular level, and modulating this target may promote cell survival and alleviate specific age-related changes. The growing number of evidence also suggests a causal relationship between mitochondrial dysfunction and AD (13). Influencing the metabolic control may, thus, provide an alternative to the amyloid- or tau-targeting pathways for AD interventions. 

Though the data demonstrated prevalent inhibition of ATP synthase, interaction with other binding partners was also studied. Several other mitochondria-associated proteins were identified in the samples suggesting that J147 modulates stress-related mitochondrial Ca²⁺ flux, an abundance of which was also connected with neuronal damage in AD.

Interestingly, the studies also demonstrated (14,15) the role of ATP synthase inhibition in increasing the lifespan of worms and flies via further reduction of mTOR (mammalian target of rapamycin) signaling. The researchers tested if those effects were repeated with J147 and observed a 12.5% lifespan extension in the fruit flies (12). Further exploration in SAMP8 mice showed that J147 stabilized and reversed age-associated changes at the molecular level. These results imply not only that aging and dementia are more closely related than usually is thought but also that J147 holds potential for multiple other anti-aging applications.

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Clinical studies

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J147 presents a unique drug candidate due to its multitask profile showing the ability to enhance memory, potentiate learning, and maintain synaptic health while lowering biochemical markers of inflammation and soluble amyloid levels (16). Moreover, J147 has good chemical properties for a drug, high oral availability, and a promising safety profile. All these make J147 highly relevant to human AD.

All these factors led J147 to the clinical trial, with Phase I ending in February 2020 (17). Phase I was a randomized, double-blind, placebo-controlled, parallel-design study aiming to assess the safety profile, pharmacokinetics, and optimal dosage of J147 in healthy subjects. The study included a single ascending dose in healthy young and elderly subjects. Healthy elderly subjects should have received a dose found to be safe in the younger subjects. The study intended to include 64 healthy people.

Though Phase I was successfully finished, the results have not yet been disclosed. J147 continues to be extensively studied both for its anti-AD activity and potential geroprotective usage, and Phase II of trials is, hopefully, expected in the future.

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Conclusions

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J147 is a promising drug candidate against AD – a disease that affects millions but still lacks reliable therapeutics. In addition, studies of J147 also yielded a crucial insight into links between AD and aging, as well as ways to screen for novel geroprotectors. Though the following stages of clinical trials are still ahead, the potential applications of discoveries already made on this path give hope for the emergence of novel ways not only to treat neurodegenerative conditions but to increase lifespan as well.

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References

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2.         Wegmann S, Biernat J, Mandelkow E. A current view on Tau protein phosphorylation in Alzheimer’s disease. Curr Opin Neurobiol. 2021 Aug;69:131–8.

3.         for the SCarlet RoAD Investigators, Ostrowitzki S, Lasser RA, Dorflinger E, Scheltens P, Barkhof F, et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther. 2017 Dec;9(1):95.

4.         Prati F, Bottegoni G, Bolognesi ML, Cavalli A. BACE-1 Inhibitors: From Recent Single-Target Molecules to Multitarget Compounds for Alzheimer’s Disease: Miniperspective. J Med Chem. 2018 Feb 8;61(3):619–37.

5.         Pedersen JT, Sigurdsson EM. Tau immunotherapy for Alzheimer’s disease. Trends Mol Med. 2015 Jun;21(6):394–402.

6.         Cummings J, Lee G, Zhong K, Fonseca J, Taghva K. Alzheimer’s disease drug development pipeline: 2021. Alzheimers Dement Transl Res Clin Interv [Internet]. 2021 Jan [cited 2022 May 31];7(1). Available from: https://onlinelibrary.wiley.com/doi/10.1002/trc2.12179

7.         Lalli G, Schott JM, Hardy J, De Strooper B. Aducanumab: a new phase in therapeutic development for Alzheimer’s disease? EMBO Mol Med [Internet]. 2021 Aug 9 [cited 2022 Apr 27];13(8). Available from: https://onlinelibrary.wiley.com/doi/10.15252/emmm.202114781

8.         Kepchia D, Currais A, Dargusch R, Finley K, Schubert D, Maher P. Geroprotective effects of Alzheimer’s disease drug candidates. Aging. 2021 Feb 15;13(3):3269–89.

9.         Prior M, Chiruta C, Currais A, Goldberg J, Ramsey J, Dargusch R, et al. Back to the Future with Phenotypic Screening. ACS Chem Neurosci. 2014 Jul 16;5(7):503–13.

10.       Currais A, Goldberg J, Farrokhi C, Chang M, Prior M, Dargusch R, et al. A comprehensive multiomics approach toward understanding the relationship between aging and dementia. Aging. 2015 Nov 11;7(11):937–55.

11.       Prior M, Goldberg J, Chiruta C, Farrokhi C, Kopynets M, Roberts AJ, et al. Selecting for neurogenic potential as an alternative for Alzheimer’s disease drug discovery. Alzheimers Dement. 2016 Jun;12(6):678–86.

12.       Goldberg J, Currais A, Prior M, Fischer W, Chiruta C, Ratliff E, et al. The mitochondrial ATP synthase is a shared drug target for aging and dementia. Aging Cell. 2018 Apr;17(2):e12715.

13.       Picone P, Nuzzo D, Caruana L, Scafidi V, Di Carlo M. Mitochondrial Dysfunction: Different Routes to Alzheimer’s Disease Therapy. Oxid Med Cell Longev. 2014;2014:1–11.

14.       Sun X, Wheeler CT, Yolitz J, Laslo M, Alberico T, Sun Y, et al. A Mitochondrial ATP Synthase Subunit Interacts with TOR Signaling to Modulate Protein Homeostasis and Lifespan in Drosophila. Cell Rep. 2014 Sep;8(6):1781–92.

15.       Chin RM, Fu X, Pai MY, Vergnes L, Hwang H, Deng G, et al. The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature. 2014 Jun;510(7505):397–401.

16.       Chen Q, Prior M, Dargusch R, Roberts A, Riek R, Eichmann C, et al. A Novel Neurotrophic Drug for Cognitive Enhancement and Alzheimer’s Disease. Iijima KM, editor. PLoS ONE. 2011 Dec 14;6(12):e27865.

17.       J147: Phase I Clinical Trial [Internet]. [cited 2022 May 31]. Available from: https://clinicaltrials.gov/ct2/show/study/NCT03838185

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