(-)-phenserine and inhibiting pre-programmed cell death: In pursuit of a novel intervention for Alzheimer’s disease

Robert E. Becker, Nigel H. Greig, Debomoy Lahiri, Joseph Bledsoe, Sarah Majercik, Clive Ballard, Dag Aarsland, Lon S. Schneider, Douglas Flanagan, Ramprakash Govindarajan, Mary Sano, Luigi Ferrucci, Dimitrios Kapogiannis

Research output: Contribution to journalReview article

Abstract

Background: Concussion (mild) and other moderate traumatic brain injury (TBI) and Alzheimer’s disease (AD) share overlapping neuropathologies, including neuronal pre-programmed cell death (PPCD), and clinical impairments and disabilities. Multiple clinical trials targeting mechanisms based on the Amyloid Hypothesis of AD have so far failed, indicating that it is prudent for new drug developments to also pursue mechanisms independent of the Amyloid Hypothesis. To address these issues, we have proposed the use of an animal model of concussion/TBI as a supplement to AD transgenic mice to provide an indication of an AD drug candidate’s potential for preventing PPCD and resulting progression towards dementia in AD. Methods: We searched PubMed/Medline and the references of identified articles for background on the neuropathological progression of AD and its implications for drug target identification, for AD clinical trial criteria used to assess disease modification outcomes, for plasma biomarkers associated with AD and concussion/TBI, neuropathologies and especially PPCD, and for methodological critiques of AD and other neuropsychiatric clinical trial methods. Results: We identified and address seven issues and highlight the Thal-Sano AD ‘Time to Onset of Impairment’ Design for possible applications in our clinical trials. Diverse and significant pathological cascades and indications of self-induced neuronal PPCD were found in concussion/TBI, anoxia, and AD animal models. To address the dearth of peripheral markers of AD and concussion/TBI brain pathologies and PPCD we evaluated Extracellular Vesicles (EVs) enriched for neuronal origin, including exosomes. In our concussion/TBI, anoxia and AD animal models we found evidence consistent with the presence of time-dependent PPCD and (-)-phenserine suppression of neuronal self-induced PPCD. We hence developed an extended controlled release formulation of (-)-phenserine to provide individualized dosing and stable therapeutic brain concentrations, to pharmacologically interrogate PPCD as a drug development target. To address the identified problems potentially putting any clinical trial at risk of failure, we developed exploratory AD and concussion/TBI clinical trial designs. Conclusions: Our findings inform the biomarker indication of progression of pathological targets in neurodegenerations and propose a novel approach to these conditions through neuronal protection against self-induced PPCD.

LanguageEnglish (US)
Pages883-891
Number of pages9
JournalCurrent Alzheimer Research
Volume15
Issue number9
DOIs
StatePublished - Jan 1 2018

Fingerprint

Alzheimer Disease
Cell Death
Clinical Trials
Animal Models
phenserine
Amyloid
Pharmaceutical Preparations
Biomarkers
Brain Concussion
Exosomes
Brain Hypoxia
Brain
Traumatic Brain Injury
PubMed
Transgenic Mice
Dementia
Pathology

Keywords

  • (-)-phenserine
  • Alzheimer’s disease
  • Apoptosis
  • Concussion
  • Exosomes
  • Extracellular vesicle biomarkers
  • Neurodegeneration
  • Neurodegenerative disorder clinical trial design
  • Pre-programmed cell death
  • Traumatic brain injury

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

(-)-phenserine and inhibiting pre-programmed cell death : In pursuit of a novel intervention for Alzheimer’s disease. / Becker, Robert E.; Greig, Nigel H.; Lahiri, Debomoy; Bledsoe, Joseph; Majercik, Sarah; Ballard, Clive; Aarsland, Dag; Schneider, Lon S.; Flanagan, Douglas; Govindarajan, Ramprakash; Sano, Mary; Ferrucci, Luigi; Kapogiannis, Dimitrios.

In: Current Alzheimer Research, Vol. 15, No. 9, 01.01.2018, p. 883-891.

Research output: Contribution to journalReview article

Becker, RE, Greig, NH, Lahiri, D, Bledsoe, J, Majercik, S, Ballard, C, Aarsland, D, Schneider, LS, Flanagan, D, Govindarajan, R, Sano, M, Ferrucci, L & Kapogiannis, D 2018, '(-)-phenserine and inhibiting pre-programmed cell death: In pursuit of a novel intervention for Alzheimer’s disease' Current Alzheimer Research, vol. 15, no. 9, pp. 883-891. https://doi.org/10.2174/1567205015666180110120026
Becker, Robert E. ; Greig, Nigel H. ; Lahiri, Debomoy ; Bledsoe, Joseph ; Majercik, Sarah ; Ballard, Clive ; Aarsland, Dag ; Schneider, Lon S. ; Flanagan, Douglas ; Govindarajan, Ramprakash ; Sano, Mary ; Ferrucci, Luigi ; Kapogiannis, Dimitrios. / (-)-phenserine and inhibiting pre-programmed cell death : In pursuit of a novel intervention for Alzheimer’s disease. In: Current Alzheimer Research. 2018 ; Vol. 15, No. 9. pp. 883-891.
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T2 - Current Alzheimer Research

AU - Becker, Robert E.

AU - Greig, Nigel H.

AU - Lahiri, Debomoy

AU - Bledsoe, Joseph

AU - Majercik, Sarah

AU - Ballard, Clive

AU - Aarsland, Dag

AU - Schneider, Lon S.

AU - Flanagan, Douglas

AU - Govindarajan, Ramprakash

AU - Sano, Mary

AU - Ferrucci, Luigi

AU - Kapogiannis, Dimitrios

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N2 - Background: Concussion (mild) and other moderate traumatic brain injury (TBI) and Alzheimer’s disease (AD) share overlapping neuropathologies, including neuronal pre-programmed cell death (PPCD), and clinical impairments and disabilities. Multiple clinical trials targeting mechanisms based on the Amyloid Hypothesis of AD have so far failed, indicating that it is prudent for new drug developments to also pursue mechanisms independent of the Amyloid Hypothesis. To address these issues, we have proposed the use of an animal model of concussion/TBI as a supplement to AD transgenic mice to provide an indication of an AD drug candidate’s potential for preventing PPCD and resulting progression towards dementia in AD. Methods: We searched PubMed/Medline and the references of identified articles for background on the neuropathological progression of AD and its implications for drug target identification, for AD clinical trial criteria used to assess disease modification outcomes, for plasma biomarkers associated with AD and concussion/TBI, neuropathologies and especially PPCD, and for methodological critiques of AD and other neuropsychiatric clinical trial methods. Results: We identified and address seven issues and highlight the Thal-Sano AD ‘Time to Onset of Impairment’ Design for possible applications in our clinical trials. Diverse and significant pathological cascades and indications of self-induced neuronal PPCD were found in concussion/TBI, anoxia, and AD animal models. To address the dearth of peripheral markers of AD and concussion/TBI brain pathologies and PPCD we evaluated Extracellular Vesicles (EVs) enriched for neuronal origin, including exosomes. In our concussion/TBI, anoxia and AD animal models we found evidence consistent with the presence of time-dependent PPCD and (-)-phenserine suppression of neuronal self-induced PPCD. We hence developed an extended controlled release formulation of (-)-phenserine to provide individualized dosing and stable therapeutic brain concentrations, to pharmacologically interrogate PPCD as a drug development target. To address the identified problems potentially putting any clinical trial at risk of failure, we developed exploratory AD and concussion/TBI clinical trial designs. Conclusions: Our findings inform the biomarker indication of progression of pathological targets in neurodegenerations and propose a novel approach to these conditions through neuronal protection against self-induced PPCD.

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KW - (-)-phenserine

KW - Alzheimer’s disease

KW - Apoptosis

KW - Concussion

KW - Exosomes

KW - Extracellular vesicle biomarkers

KW - Neurodegeneration

KW - Neurodegenerative disorder clinical trial design

KW - Pre-programmed cell death

KW - Traumatic brain injury

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