Promising Alzheimer’s Treatment: Hope for CJD Gary Landreth Department of Neurosciences Case Western Reserve University • First described by Dr. Alois Alzheimer in 1907. • Most common cause of dementia in the elderly • The 6th most common cause of death in the US • Characterized by progressive loss of cognitive ability and dementia • Extensive pathology-senile plaques and neurofibrillary tangles • Average length between diagnosis and death is 8 years Alzheimer’s Disease • Presently ~5 million cases in the United States • Prevalence in individuals >85 years old is estimated to be 40-50% • Estimated Cost 2009 = $150B Alzheimer’s Disease Alzheimer’s Disease: Pathological changes occur years before symptoms appear Jacks et al., 2010 Alzheimer’s Disease One of the most prominent features of Alzheimer’s disease is the extensive deposition of a waxy substance, termed beta amyloid within the brain. ab g Ab peptide 1 40 or 42 aa APP b-pleated sheet NH2 COOH Ab Fibril Amyloid Precursor Protein Ab Peptide Ab Plaque Secretase Cleavage Ab Oligomers Neuronal APP processing and amyloid fibril formation Impaired Aβ clearance from the brain is responsible for late onset AD Vol. 330 :1774, Dec. 9, 2010 Dec. 13, 2010 The Vanishing Mind: Insights give hope for new attacks on Alzheimer’s Gina Kolata For years, it seemed, the problem in Alzheimer’s was that brain cells were making too much amyloid. But now, a surprising new study has found that that view appears to be wrong. It turns out that most people with Alzheimer’s seem to make perfectly normal amounts of amyloid. They just can’t get rid of it. It’s like an overflowing sink caused by a clogged drain instead of a faucet that does not turn off • Ab is generated at high levels in the normal brain at a rate of 7.6%/hr • Ab is cleared from the brain at a rate of 8.3%/hr. (Bateman et al. NatMed 12:856, 2006) • Small perturbations of clearance will result in accumulation of Ab in the brain Ab clearance from the CNS is reduced by appx. 30% in individuals with AD (Mawuenyega et al. 2010) Sporadic, late-onset AD is associated with impaired Ab clearance from the brain Extracellular Degradation: Insulin Degrading Enzyme (IDE) Intracellular degradation: Neprilysin Neprilysin IDE IDE Neprilysin Intrinsic Mechanisms of Ab clearance Microglia Ab degradation Neuron Neuron soluble Aß clearance fibrillar Aß plaque synaptic deficits cognitive impairment Alzheimer’s Disease arises from the inability to clear amyloid from the brain healthy brain Alzheimer’s Disease Age-related Impairment X impaired Degradation/ clearance Neuron soluble Aß Degradation/ clearance ApoE/HDL + healthy brain Clearance of amyloid requires ApoE We discovered that ApoE is a critical component of the normal, physiological mechanism through which Ab is cleared from the brain. Thus, if ApoE levels in the brain can be elevated, this should stimulate the removal of Ab from the brain, preserving cognition and memory. Bexarotene ApoE/HDL soluble Aß Degradation/ clearance + Nuclear receptors in the brain act to stimulate the synthesis of ApoE and thus clearance of Ab Highly specific RXR agonist Bexarotene is fully BBB penetrant Orally delivered FDA approved for treatment of T cell lymphoma Bexarotene (TargretinTM) ) In Vivo Microdialysis Measure Interstitial Fluid (ISF) levels of soluble Aβ Modified from: http://www.currentprotocols.com/protocol/ns0702 Does Bexarotene clear soluble Aβ from the brains of an AD mouse model?How long does 1 dose of bexarotene last? RXR agonist treatment rapidly clears preexisting plaques from the brain Cortex Hippocampus Bex14daysVehicle 6 month old APP/PS1 Thioflavin S Bexarotene stimulates microglial phagocytosis of Ab Ab Microglia Nuclei 9 month old APP/PS1 mice 72 hrs treatment with Bexarotene Bexarotene rapidly stimulates the phagocytic removal of amyloid plaques Bexarotene Treatment Restores Nesting Behavior 3 day treatment Morris Water Maze Bexarotene Treatment Improves Memory in Mouse Models of AD 7-8 month APPPS1-21 9 month APP/PS1 90 day treatment 20 day treatment Proof of Mechanism Clinical Biomarker Trial of Bexarotene in Humans: A randomized, placebo-controlled study of Ab and ApoE metabolism in the nervous system Cost: $1.16M 100% of funding is in place. Expect to initiate trial September, 2012 4 months to completion Translation into Clinical Trials SILK Technology Trial Endpoints • 12 Normal Subjects • 6 subjects each on placebo or bexarotene • Blood and CSF drawn hourly for 36 hrs • Biomarkers: – Ab clearance rate – ApoE biosynthesis rate – Brain and plasma levels of bexarotene The use of an FDA-approved drug dramatically speeds the development of this therapy for AD Discovery of new biological mechanisms and therapies will allow their application to other CNS disorders NR RXR Stroke Fronto- temporal dementias Epilepsy (NDG- related) Traumatic Brain Injury Parkinson’s Disease Prion Diseases Alzheimer’s Disease Down Syndrome Rationale for use in CJD • Bexatrotene suppresses the glial inflammatory responses to neuronal dysfunction and death • Bexarotene acts in neurons to promote the clearance of amyloid, thus it is possible that it may clear prion intraneuronal deposits • Drug may promote microglial-mediated phagocytosis of extracellular prion deposits • Drugs of this class exhibit broad neuroprotective actions