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      The Value of Herbarium Collections to the Discovery of Novel Treatments for Alzheimer’s Disease, a Case Made With the Genus Eriodictyon

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          Abstract

          Plants, in particular those with a history in traditional medicine, hold enormous potential as sources of new therapies for dementias such as Alzheimer’s disease (AD). The largest collections of plants can be found in herbaria all over the world, but the value of these collections to AD drug discovery has been significantly neglected. As a proof of principle, we investigated the neuroprotective activity of herbarium specimens of Eriodictyon (yerba santa), a genus with a long history of usage by the indigenous tribes in California to treat respiratory and age-related complications. Dichloromethane extracts were prepared from leaves of 14 Eriodictyon taxa preserved in the SD Herbarium located at the San Diego Natural History Museum. The extracts were tested for neuroprotection in nerve cells against oxytosis and ferroptosis and for anti-inflammatory activity in brain microglial cells exposed to bacterial lipopolysaccharide. In parallel, the levels of the flavanones sterubin, eriodictyol and homoeriodictyol were measured by mass spectrometry. Several Eriodictyon species presented strong neuroprotective and anti-inflammatory activities. The protective properties of the extracts correlated with the amount of sterubin, but not with eriodictyol or homoeriodictyol, indicating that sterubin is the major active compound in these species. The occurrence of eriodictyol and homoeriodictyol may be predictive of the phylogenetic relationship between members in the genus Eriodictyon. The data offer insight into the traditional use of yerba santa across indigenous tribes in California, while demonstrating the value of herbarium collections for the discovery of novel therapeutic compounds for the treatment of neurodegenerative diseases.

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          The mitochondrial ATP synthase is a shared drug target for aging and dementia

          Summary Aging is a major driving force underlying dementia, such as that caused by Alzheimer's disease (AD). While the idea of targeting aging as a therapeutic strategy is not new, it remains unclear how closely aging and age‐associated diseases are coupled at the molecular level. Here, we discover a novel molecular link between aging and dementia through the identification of the molecular target for the AD drug candidate J147. J147 was developed using a series of phenotypic screening assays mimicking disease toxicities associated with the aging brain. We have previously demonstrated the therapeutic efficacy of J147 in several mouse models of AD. Here, we identify the mitochondrial α‐F1‐ATP synthase (ATP5A) as a target for J147. By targeting ATP synthase, J147 causes an increase in intracellular calcium leading to sustained calcium/calmodulin‐dependent protein kinase kinase β (CAMKK2)‐dependent activation of the AMPK/mTOR pathway, a canonical longevity mechanism. Accordingly, modulation of mitochondrial processes by J147 prevents age‐associated drift of the hippocampal transcriptome and plasma metabolome in mice and extends lifespan in drosophila. Our results link aging and age‐associated dementia through ATP synthase, a molecular drug target that can potentially be exploited for the suppression of both. These findings demonstrate that novel screens for new AD drug candidates identify compounds that act on established aging pathways, suggesting an unexpectedly close molecular relationship between the two.
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            A Novel Neurotrophic Drug for Cognitive Enhancement and Alzheimer's Disease

            Currently, the major drug discovery paradigm for neurodegenerative diseases is based upon high affinity ligands for single disease-specific targets. For Alzheimer's disease (AD), the focus is the amyloid beta peptide (Aß) that mediates familial Alzheimer's disease pathology. However, given that age is the greatest risk factor for AD, we explored an alternative drug discovery scheme that is based upon efficacy in multiple cell culture models of age-associated pathologies rather than exclusively amyloid metabolism. Using this approach, we identified an exceptionally potent, orally active, neurotrophic molecule that facilitates memory in normal rodents, and prevents the loss of synaptic proteins and cognitive decline in a transgenic AD mouse model.
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              Back to the future with phenotypic screening.

              There are no disease-modifying drugs for any old age associated neurodegenerative disease or stroke. This is at least in part due to the failure of drug developers to recognize that the vast majority of neurodegenerative diseases arise from a confluence of multiple toxic insults that accumulate during normal aging and interact with genetic and environmental risk factors. Thus, it is unlikely that the current single target approach based upon rare dominant mutations or even a few preselected targets is going to yield useful drugs for these conditions. Therefore, the identification of drug candidates for neurodegeneration should be based upon their efficacy in phenotypic screening assays that reflect the biology of the aging brain, not a single, preselected target. It is argued here that this approach to drug discovery is the most likely to produce safe and effective drugs for neurodegenerative diseases.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                10 March 2020
                2020
                : 11
                : 208
                Affiliations
                [1] 1Cellular Neurobiology Laboratory, Salk Institute for Biological Studies , La Jolla, CA, United States
                [2] 2Mass Spectrometry Core, Salk Institute for Biological Studies , La Jolla, CA, United States
                [3] 3Department of Botany, San Diego Natural History Museum , San Diego, CA, United States
                Author notes

                Edited by: Adolfo Andrade-Cetto, National Autonomous University of Mexico, Mexico

                Reviewed by: Daniel Załuski, Nicolaus Copernicus University in Toruń, Poland; Tinde Van Andel, Naturalis Biodiversity Center, Netherlands

                *Correspondence: Jon Rebman, jrebman@ 123456sdnhm.org

                This article was submitted to Ethnopharmacology, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2020.00208
                7076189
                ae3959b4-6b5c-4adc-8026-0be438a6a3cc
                Copyright © 2020 Maher, Fischer, Liang, Soriano-Castell, Pinto, Rebman and Currais.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 21 December 2019
                : 14 February 2020
                Page count
                Figures: 2, Tables: 2, Equations: 0, References: 32, Pages: 9, Words: 0
                Funding
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: AG046153
                Award ID: AG054714
                Award ID: NS106305
                Award ID: AI104034
                Award ID: P30 014195
                Categories
                Pharmacology
                Brief Research Report

                Pharmacology & Pharmaceutical medicine
                alzheimer’s disease,herbarium,neurodegenerative disorders,neuroprotection,traditional medicine california

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