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Alzheimer's disease - finding new treatments
Transcript of Alzheimer's disease - finding new treatments
- blocks enzyme inhibitors
- reduces plasma and brain A
levels in transgenic mice 2. RAGE inhibitor
- BBB membrane transporter:
+ secondary benefits Immunotherapy Inhibiting Aβ aggregation Enhancing A clearance Modulation of Aβ production First target in amyloid pathway - In vivo studies showed could reduce plasma and soluble brain A in mice after only a few hours. 2001. Recent announcemnet of y-secretase inhibitor (semagacestat) into a phase 111 trial. BACE1 - knock out mice has lead to the abscence of amyloid production Inhibitor development remians challenging - only 1 compnay has reported clinical data witha BACE1 inhibitor β Intraneural tangles containing hyperphosphyorylated tau are a hallmark of AD pathology Inhibition of aggregation is conceptually appealing due to tau aggregates being very detrimental. Difficult to target therapeutically neprilysin insulin degrading
enzyme plasmin Several kinase inhibitors are being investigated in pre clinical studies
Is hyerphophorylated tau critical to pathology
Can a specific kinase be generated ?
The ubiquitous expression of these kinases along with their activity in countless cellular function makes targeting difficult. A 1. Bapineuzumab 2. Solanezumab
3. IV IgG Aβ Aβ Aβ - - metal tramiprosate The metal hypothesis trace metals contribute to A pathology Fe Cu Zn increased levels in AD Antioxidants Metal chelators Metal complexes Metal-protein
attenuating compounds vitamin E desferroxamine PDTC Clioquinol Tau aggregation inhibitors The most clinically advanced TAi are AL-108 (intra nasal formulation) and 'Remember'
Mechanism - in vitro studies suggest both drugs increases soluble Tau levels to prevent Tau aggregation leading to improved cognition Data from a phase 2 trial of Al-108 in 144 patients with AD
safe and well tolerated (15 mg bd)
resulted in a significant and lasting improvement of short term and working memory A recently announced TAi is 'Remember' - methylthioninium chloride (histochemical dye methylene blue)
Data from a phase 2 placebo controlled clinical trial in 332 subjects (mild-moderate AD)
Significant AD Assessment cognitive score differences relative to placebo were observed. Anti inflammatory approaches the most confusing area of AD therapy.
Should it be targeted? Background Activated microglia are strongly associated with senile plaques and that many inflammatory mediators, including prostaglandins are upregulated in affected areas of AD brain. This lead to the hypothesis that NSAIDs could be beneficial. This idea was supported by the lower incidence of AD in patients with arthritis (most use NSAIDs) Theory Emerging evidence Evidence from multiple case-control and population based studies supported a roughly 50% reduction in AD risk (in long term use) Clinical trials Clinical trials in AD have been disappointing
both COX2 and mixed COX1/2 all failed to show therapeutic benefit.
However NSAIDs may be useful in primary prevention of AD and not treatment Should one redirect and not suppress the inflammatory response Current NICE Guidelines 2009 Mild - Moderate AD:
10 -20 Points on MMSE Acetylcholinesterase inhibitors Donepezil, galantamine and rivastigmine Review MMSE every 6/12: must remain above 10 In clinical trials:
Moderate - Severe AD NMDA - Receptor Antagonists Memantine The Pathophysiology of AD Pathology Amyloid plaques
Neurofibrillary tangles - filaments of tau protein Genetics Amyloid precurser protein (APP)
Presenilin 1 and 2 ( PS1 and PS2)
Apolipo-protein E (APOE) Environmental Risk factors: smoking, hypertension, diabetes, obesity.
Depression metal hypothesis The future Neurotransmitters Acetylcholine Amyloid Plaque Formation Tau Protein - Neurofibrillary Tangle Formation Treatment: symptomatic v disease modifying A1-108 Remember References Wischik C & Staff R. (2009). Challenges in the conduct of disease-modifying trials in AD: practical experience from a phase 2 trial of Tau-aggregation inhibitor therapy. The journal of nutrition, health & aging 13, 367-369.
Citron M. (2010). Alzheimer's disease: strategies for disease modification. Nature reviews 9, 387-398.
Brain et al. (2009) Pharmacotherapeutics targets in Alzheimer's disease. Journal of cellular and molecular medicine. 1, 61-86.
McGeer PL & McGeer EG. (2007). NSAIDs and Alzheimer disease: epidemiological, animal model and clinical studies. Neurobiology of aging 28, 639-647.
National institute for clinical excellence 2009. Dementia: Supporting people with dementia and their carers in health and social care.
The British Psychological Society and Gaskel.
Joint Formulary Committee. British National Formulary. 60th ed. London: British Medical Association and Royal Pharmaceutical Society; 2010.