Emerging Treatments in Alzheimer’s Disease Abby Harrelson Advisor: Sheldon Kopperl

Overview Background Pathology of Alzheimer’s Disease Diagnosis Current Treatments Newer therapies

Background of AD Prevalence in United States Risk factors Diagnosis

Brain Scan Images

Pathology Three pathways Aggregation of protein Severe neuronal death tau protein amyloid-β 42 peptide Severe neuronal death

Current Treatments Cholinesterase inhibitors used in mild to moderate cases Donepezil (Aricept) N-methyl-D-aspartate receptor antagonist used in moderate to severe cases Memantine (Namenda)

New Targets Selective inhibitors Enzyme therapy Antioxidants Hormones Antidepressants Immunotherapy Antiviral agents Allopregnanolone Combined therapies

Selective Inhibitors Selective inhibitors of acetyl cholinesterase 3 binding sites Aromatic gorge Active site Esteratic or anionic site Anionic site most promising binding site for treatment options

Antioxidants Studied as preventative therapy Dietary Options: Folate supplementation Vitamins C and E Pharmaceutical Options: Mitochondrial antioxidants CoQ10 vs. MitoQ

Hormones Increased incidence of AD in females Direct link been found between AD and luteinizing hormone Leuprolide acetate

Immunotherapy Amyloid- (A) immunotherapy Anti-inflammatory interleukin-4 Trial done on mice Found that IL-4 stimulated neurogenesis

Antiviral Agents Herpes simplex virus 1 Causes herpes simplex encephalitis, impacts same part of brain as Alzheimer’s Antiviral to treat AD Antiviral agents target viral DNA replication Determined tau formation dependent on this process Tested 3, all inhibited tau formation

Allopregnanolone Metabolite of progesterone and a modulator of GABA receptors Most affective at earliest stages of disease The appearance of Aβ plaques coincides with end of efficacy

Combined Therapies Donepezil + natural hirudin Donepezil + Memantine Combined treatment showed significant decrease in ADAS-cog score Donepezil + Memantine Combined treatment did not show significant decrease in ADAS-cog score

Summary Several new treatments have promising outlooks Need further research Clinical trials: combined therapy Easier diagnosis and treatment of prodromal AD

Primary References Svedruzic Z, Popovic K, Smoljan I, Sendula-Jengic V. 2012. Modulation of -secretase activity by multiple enzyme-substrate interactions: implications in pathogenesis of Alzheimer’s disease. PLoS ONE. 7:3. Li DQ, Zhou YP, Yang H. 2012. Donepezil combined with natural hirudin improves the clinical symptoms of patients with mild-to- moderate Alzheimer’s disease: a 20-week open-label pilot study. Int J Med Sci. 9(3):248-255. Chen S, Wang J, Irwin R, Yao J, Liu L, Brinton R. 2011. Allopregnanolone promotes regeneration and reduces -amyloid burden in a preclinical model of Alzheimer’s disease. PLoS ONE. 6(8):e24293. Wozniak M, Front A, Preston C, Itzhaki R. 2011. Antivirals reduce the formation of key Alzheimer’s disease molecules in cell cultures acutely infected with herpes simplex virus type 1. PLoS ONE. 6(10):e25152. Howard R, et al. 2012. Donepezil and memantine for moderate- to-severe Alzheimer’s disease. N Engl J Med. 366:893-903.