Early Prevention of Alzheimerʼs Disease? Scientific Justification and Current Strategies

Karen Ritchie

University of Edinburgh, United Kingdom

Epidemiological studies suggest a complex interaction of risk and protective factors which contribute differentially to the probability and timing of Alzheimerʼs disease (AD) onset. By modeling intervention scenarios it may be demonstrated that public health prevention strategies focusing on the most potent and potentially reversible risk factors could have a highly significant impact on disease incidence over the coming decade. This research has been validated across several countries and integrated into the recent Lancet report on the future of AD management. Exposure to these risk factors occur, however, primarily in middle age suggesting that strategies to prevent or delay disease onset should be carried out much earlier than is currently the case. Prevention programs carried out in the preclinical phase of AD will require the development of outcome measures able to detect brain changes in the absence of clinical signs. Recommendations for the design of preclinical prevention strategies are presented along with early results from the PREVENT-AD multi-site research project.

Biography:
Professor Karen Ritchie is a neuropsychologist and epidemiologist, who began her career with the Health Services Evaluation Unit, University of Oxford (Sir Richard Doll) and the Social Psychiatry Research Unit, MRC Australia. She is currently Director of the French National Institute of Medical Research (INSERM), Research Unit 1061 (Neuropsychiatry) in Montpellier. The research work currently being undertaken by this group includes population, clinical and molecular studies of neurological and psychiatric disorders notably dementia, depression, post-traumatic stress disorder, suicide, sleep pathologies, and care evaluation. She has also acted as consultant to the Mental Health Division of the World Health Organization and is a member of the Board of the European Institute for Womenʼs Health. She is currently also Visiting Professor, Centre for Clinical Brain Sciences, University of Edinburgh.

Potential Gene, Drugs and Stem Cell Therapy at Critical Period in Alzheimerʼs Disease Mice

Yoo-Hun Suh

Neuroscience Research Institute of Gachon University, Korea

Alzheimerʼs disease (AD) is characterized by the accumulation of amyloid plaques and neurofibrillary tangles accompanied by cognitive dysfunction. To investigate the regulatory genes responsible for the neuropathology in AD, we performed microarray analysis in APPV717I-CT100 transgenic mice and isolated the S100a9 gene. These results clearly show that the upregulation of S100a9 gene plays an important role in the neuropathology and memory impairment in AD, suggesting that the regulation of this gene has a therapeutic potential for AD. We found that Dehydroevodiamine×HCI (DHED), Carboxy DHED, Minocycline BT11 and SF-6 had neuroprotective, memory or motor enhancing activities using various in vitro and in vivo models. DHED might be one of the potential therapeutic candidates for AD. We also examined whether intracerebrally or intravenously transplanted human adipose-derived stem cells (hASCs) could have therapeutic or preventive effects in AD/PD mice model. We demonstrated that intracerebral or intravenous injection of hASCs rescued memory deficit and gave benefits of blocking the pathogenesis in the brain of Tg mice by reducing the number of plaques and neuropathology. Hence, we demonstrated that hASCs are expected to be preventive and therapeutic approach for AD & PD. However, the optimal stage of the disease for stem cell transplantation to have a therapeutic effect has yet to be determined. Overall this study underscores that stem cell therapy at optimal time frame is crucial to obtain maximal therapeutic effects that can restore functional deficits or stop the progression of AD & PD.

Biography:
Professor Yoo-Hun Suh is now Chaired Professor and President of the Neuroscience Research Institute of Gachon University. He was the founding president of Korea Brain Research Institute. He won Koreaʼs Most Distinguished Scientist Award, the National Government Medals and other many prizes. He was selected one of 20 outstanding Korean Medical Scientists and one of 21 outstanding Korean Scholars of the 21st Century. He is an editor and editorial board member for 6. He first cloned the gene for epinephrine synthesizing enzyme, PNMT and has greatly contributed to the discovery of a new potential gene and factors for AD, the development of potential stem cell and drugs for AD and PD.

The Enigma of Eroomʼs Law and the Wall Street Math Stifling Alzheimerʼs Drug Discovery

Max Tokarsky

Founder and CEO of InvestAcure, USA

As the prevalence of Alzheimerʼs disease (AD) grows, so do the costs it imposes on society. Yet, despite a significant number of drugs showing promise in animal models, progress is being stifled by a breakdown in the ROI model at the clinical stage of drug discovery. For complex diseases like Alzheimerʼs research, progress depends on the trial and error of real-world Phase 1 & 2 clinical trials. Due to the high cost of clinical research, this stage of drug discovery depends on industry-led investment. The average cost of developing a new drug, per billion US dollars spent on R&D, has doubled roughly every nine years since 1950. That means, adjusted for inflation, it costs 80 times more to develop a new drug today then it did in 1950! The observation of this trend was coined Eroomʼs Law by industry analyst Jack Scannell in 2012, writing in Nature Reviews Drug Discovery. The current ROI from internal R&D in the pharmaceutical industry as a whole is an average 3.7%. For Alzheimerʼs, this model has broken down altogether and has led most major pharmaceuticals to downsize or close their Alzheimerʼs research divisions. A structural solution to the current financial model is needed if we are to make progress to a cure. InvestAcureʼs Public Benefit Corporation model offers one such solution, by transitioning investment leadership from the current Venture Capital model to micro-investment by those impacted by the disease.

Biography:
Max Tokarsky is a Founder & CEO of InvestAcure, PBC. Max is a lifelong social entrepreneur and nonprofit executive. He is the Founder & CEO of InvestAcure, PBC, an SEC-approved RIA, with a bold plan to solve the current investment bottleneck at the clinical stage of Alzheimerʼs drug discovery. InvestAcure enables those impacted by Alzheimerʼs to partner in the search for a cure by automatically investing their spare in clinical stage pharmaceuticals spearheading research. This helps transition investment leadership from a narrow group of high-risk investors to a much larger and stable investment base, leading to more clinical trials, more drugs and drug combinations tested and progress to a cure.

Inhibition of Endocytic Pathway of BACE1 as a Therapeutic Strategy for Alzheimerʼs Disease Treatment

Beka Solomon

Tel Aviv University, Israel

Aims: Early endosomes are the first major sorting station in the endocytic pathway of BACE1 for cleavage of APP without interfering in processing of other vital substrates. The endocytic pathway is responsible for internalization and processing of cell surface APP which generates besides Aβ, the β- AICD capable of regulating transcription. Here we propose to interfere with APP-BACE1 interaction, exploiting its presence at the cell surface prior to internalization into early endosomes. The proposed approach is based on antibodies blocking the β-secretase cleavage site of APP (BBS1).The complex APP-BBS1 is stable at acidic pH and may prevent the amyloidogenic processing of APP by BACE1 in early endosomes.

Method: BBS1 antibodies raised against a chimera antigen containing only one Swedish mutation of APP, recognize both wild-type and mutated APP and do not bind to Aβ peptide. The effect of BBS1 on pathology and cognitive functions in mice model of AD was investigated.

Results: The treatment of 3xTg-AD mice with BBS1 improved the cognitive function, lowered the levels of intracellular Aβ, reduce the plaques size, phosphorylated tau and inflammation .The antibodies down regulate apoptotic genes as P53 and GSK3β which are involved in neuronal apoptosis.

Conclusion: Amyloid-β peptide is not the only active component for AD neurotoxicity and the β-AICD which regulates the transcription of genes involved in cytoskeletal dynamics and apoptosis contributing also to AD pathology. Inhibition of endocytic pathway of BACE1 via antibodies blocking the β-secretase cleavage site of APP may prevent amyloidogenic processing of APP and thus became a therapeutic strategy for AD treatment.

Biography:
Professor Beka Solomon earned her Ph.D. in 1976 from the Weizmann Institute of Science, Rehovoth, Israel. She joined Tel-Aviv University in 1979 following post-doctoral studies and training periods at Harvard Medical School and Brigham and Womenʼs Hospital, Boston, USA. She is a member of the editorial board of Drugs of Today, Recent Patents on CNS Drug Discovery, of Neurodegenerative Diseases and Journal of Alzheimerʼs Disease. She was awarded the prestigious Zenith Award of the Alzheimer Association, and received the Dana Foundation Award for Neuroimmunology. In 2007 she was included in Scientific Americanʼs List of 50 of the Worldʼs Leading Innovators.