![]() ![]() The neurotrophic and memory-enhancing activities of J147 are associated with an increase in the level of brain derived neurotrophic factor (BDNF) along with the expression of BDNF-responsive proteins, the enhancement of long term potentiation (LTP), synaptic protein preservation, the reduction of markers for oxidative stress and inflammation, the reduction of amyloid plaques, and lower levels of soluble Aβ 1-42 and Aβ 1-40. Based upon activity in multiple CNS toxicity assays, we identified an exceptionally potent, orally active, neurotrophic molecule called J147 that facilitates memory in normal rodents, and prevents the loss of synaptic proteins and cognitive decline when administered to three-month-old APP/swePS1ΔE9 mice for seven months. As potential lead drug candidates, we generated a large number of derivatives of the curry spice curcumin, which is effective in AD transgenic mice. A series of six cell culture assays was designed to mimic multiple old-age-associated pathways of central nervous system (CNS) nerve cell damage, and drug candidates were required to show efficacy in all of these assays before being moved forward into animals. Thus, effective disease modifying treatments that also provide cognition benefits are urgently required.Īge is the greatest risk factor for developing AD, leading us to develop a drug discovery procedure that is based upon old-age-associated pathologies without requiring pre-selected molecular targets. Currently approved therapies are only symptomatic in nature, providing modest improvements in memory without altering the progression of the disease pathology. At the time when most patients are diagnosed with AD, the pathology is usually at an advanced stage. Clinically, AD results in a progressive loss of cognitive ability as well as daily function activities. 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.Īlzheimer's disease (AD) is characterized pathologically by the presence of both extracellular neuritic plaques and intracellular neurofibrillary tangles. ![]() J147 is an exciting new compound that is extremely potent, safe in animal studies and orally active. 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. 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. Resultsĭata presented here demonstrate that J147 has the ability to rescue cognitive deficits when administered at a late stage in the disease. Details on the pharmacology and safety of J147 are also included. J147 was also investigated in a scopolamine-induced model of memory impairment in C57Bl/6J mice and compared to donepezil. Cognitive behavioral assays, histology, ELISA and Western blotting were used to assay the effect of J147 on memory, amyloid metabolism and neuroprotective pathways. ![]() Aged (20-month-old) transgenic AD mice (APP/swePS1ΔE9) were fed an exceptionally potent, orally active, memory enhancing and neurotrophic molecule called J147. 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. Clearly a better approach to pre-clinical drug screening for AD is required. 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. 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. Despite years of research, there are no disease-modifying drugs for Alzheimer's disease (AD), a fatal, age-related neurodegenerative disorder. ![]()
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