PMID- 23673233
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20140520
LR  - 20211021
IS  - 1758-9193 (Print)
IS  - 1758-9193 (Electronic)
VI  - 5
IP  - 3
DP  - 2013
TI  - The neurotrophic compound J147 reverses cognitive impairment in aged Alzheimer's 
      disease mice.
PG  - 25
LID - 10.1186/alzrt179 [doi]
AB  - INTRODUCTION: Despite years of research, there are no disease-modifying drugs for 
      Alzheimer's disease (AD), a fatal, age-related neurodegenerative disorder. 
      Screening for potential therapeutics in rodent models of AD has generally relied 
      on testing compounds before pathology is present, thereby modeling disease 
      prevention rather than disease modification. Furthermore, this approach to 
      screening does not reflect the clinical presentation of AD patients which could 
      explain the failure to translate compounds identified as beneficial in animal 
      models to disease modifying compounds in clinical trials. Clearly a better 
      approach to pre-clinical drug screening for AD is required. METHODS: To more 
      accurately reflect the clinical setting, we used an alternative screening 
      strategy involving the treatment of AD mice at a stage in the disease when 
      pathology is already advanced. Aged (20-month-old) transgenic AD mice 
      (APP/swePS1DeltaE9) were fed an exceptionally potent, orally active, memory enhancing 
      and neurotrophic molecule called J147. Cognitive behavioral assays, histology, 
      ELISA and Western blotting were used to assay the effect of J147 on memory, 
      amyloid metabolism and neuroprotective pathways. J147 was also investigated in a 
      scopolamine-induced model of memory impairment in C57Bl/6J mice and compared to 
      donepezil. Details on the pharmacology and safety of J147 are also included. 
      RESULTS: Data presented here demonstrate that J147 has the ability to rescue 
      cognitive deficits when administered at a late stage in the disease. The ability 
      of J147 to improve memory in aged AD mice is correlated with its induction of the 
      neurotrophic factors NGF (nerve growth factor) and BDNF (brain derived 
      neurotrophic factor) as well as several BDNF-responsive proteins which are 
      important for learning and memory. The comparison between J147 and donepezil in 
      the scopolamine model showed that while both compounds were comparable at 
      rescuing short term memory, J147 was superior at rescuing spatial memory and a 
      combination of the two worked best for contextual and cued memory. CONCLUSION: 
      J147 is an exciting new compound that is extremely potent, safe in animal studies 
      and orally active. J147 is a potential AD therapeutic due to its ability to 
      provide immediate cognition benefits, and it also has the potential to halt and 
      perhaps reverse disease progression in symptomatic animals as demonstrated in 
      these studies.
FAU - Prior, Marguerite
AU  - Prior M
AD  - The Salk Institute for Biological Studies, Cellular Neurobiology Laboratory, 
      10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
FAU - Dargusch, Richard
AU  - Dargusch R
AD  - The Salk Institute for Biological Studies, Cellular Neurobiology Laboratory, 
      10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
FAU - Ehren, Jennifer L
AU  - Ehren JL
AD  - The Salk Institute for Biological Studies, Cellular Neurobiology Laboratory, 
      10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
FAU - Chiruta, Chandramouli
AU  - Chiruta C
AD  - The Salk Institute for Biological Studies, Cellular Neurobiology Laboratory, 
      10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
FAU - Schubert, David
AU  - Schubert D
AD  - The Salk Institute for Biological Studies, Cellular Neurobiology Laboratory, 
      10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
LA  - eng
GR  - R01 AG035055/AG/NIA NIH HHS/United States
GR  - R21 NS077201/NS/NINDS NIH HHS/United States
PT  - Journal Article
DEP - 20130514
PL  - England
TA  - Alzheimers Res Ther
JT  - Alzheimer's research & therapy
JID - 101511643
PMC - PMC3706879
EDAT- 2013/05/16 06:00
MHDA- 2013/05/16 06:01
PMCR- 2013/05/14
CRDT- 2013/05/16 06:00
PHST- 2013/01/29 00:00 [received]
PHST- 2013/03/01 00:00 [revised]
PHST- 2013/03/28 00:00 [accepted]
PHST- 2013/05/16 06:00 [entrez]
PHST- 2013/05/16 06:00 [pubmed]
PHST- 2013/05/16 06:01 [medline]
PHST- 2013/05/14 00:00 [pmc-release]
AID - alzrt179 [pii]
AID - 10.1186/alzrt179 [doi]
PST - epublish
SO  - Alzheimers Res Ther. 2013 May 14;5(3):25. doi: 10.1186/alzrt179. eCollection 
      2013.