48 th Annual Recent Advances in Neurology Disclosures UCSF Scientific Advisory Board: Neuropore Therapies Consulting: AbbVie, Catenion Neurodegenerative Disorders: Honoraria for lectures: Mechanisms and Emerging Therapies AbbVie Sponsored research funding and royalties: Bristol-Myers Squibb Lennart Mucke, MD Patents: Coinventor on Gladstone/UCSF-owned patents relating Director, Gladstone Institute of Neurological Disease to Alzheimer’s disease Joseph B. Martin Distinguished Professor of Neuroscience Note: Professor of Neurology No external financial support received for this lecture. University of California, San Francisco All drugs mentioned in this lecture are investigational relative to the potential indications discussed and have not yet been approved for these indications by the FDA. Alzheimer’s Disease Learning Objectives Alzheimer’s Association: Facts and Figures Increase Understanding of: Change in Number of Deaths In US: 5.4 Million People with AD 2000–2008 >15 Million by 2050 • Scientific, medical and socioeconomic issues raised by World: >36 Million Now neurodegenerative disorders ??? by 2050 • Need for better understanding of underlying mechanisms • Values and limitations of experimental models Current US Cost: $200 Billion/yr • Multifactorial pathogenesis of neurodegenerative disorders By 2050: >$1 Trillion/yr? • Likely requirement for a multipronged therapeutic approach – Stage dependent? – Stratified (disease and patient subtypes)? • Developing better treatments: the long and short of it 1
http://www.alzgene.org Chromosomal Location of First Genes Linked to AD All affect A � � � � production or deposition. Adapted from Lendon et al. JAMA (1997) Drug Targets Relating to the Amyloid Precursor Protein Nature 488: 96–99 (2012) A � levels in medium of APP-transfected 293T cells 2
Drug Targets Relating to the Amyloid Precursor Protein Inhibiting � � -Secretase � � May Affect the Function of Other Substrates Inhibitor “Semagacestat” failed in Phase III trial. Worsened cognitive decline! Immunization Against A � � Clears Cerebral Amyloid � � Drug Targets Relating to the Amyloid Precursor Protein Plaques in hAPP Mice and Humans with AD Schenk et al. Nature (1999), Nicoll et al. J Neuropathol Exp Neurol (2006) Blood Vessel Microglia A � � � � Plaque Antibodies 3
Immunization Against A � � � � Clears Cerebral Amyloid Dementia Is Caused by Different Diseases that Probably Plaques in hAPP Mice and Humans with AD Start Decades Before Cognitive Decline Becomes Evident Anti-A � antibodies have failed in Phase III trials. Possibly subtle benefits in patients with early AD. Blood Vessel Microglia A � � � � Impact on clinical trials! Plaque Antibodies Adapted from Dubois et al. Lancet Neurol (2007) Will Effective Treatment Require Very Early Intervention? Will Effective Treatment Require Very Early Intervention? BACE1 inhibitors BACE1 inhibitors Selective � -secretase inhibitors or modulators Selective � -secretase inhibitors or modulators Impact on Impact on Glutaminyl cyclase inhibitors Glutaminyl cyclase inhibitors Anti-A � (oligomer) antibodies Anti-A � (oligomer) antibodies clinical trials! clinical trials! Aggregation blockers Aggregation blockers Others Others Think of stroke, heart attack, diabetes, cancer and AIDS! Early treatment is key. 4
Our ApoE Experts Effect of APOE Genotype on the Risk of Caucasians to Develop Alzheimer’s Disease Around the Age of 60 Robert Mahley, MD, PhD Yadong Huang, MD, PhD Senior Investigator Senior Investigator Gladstone Institutes Gladstone Institutes Normalized Professor of Pathology and Associate Professor of Neurology, Risk Medicine, UCSF UCSF ApoE4 Probably Contributes to AD through Proteolytic Cleavage of ApoE (4>3/2) A � � � � -dependent and A � � � � -independent Mechanisms Results in Fragments that Impair Mitochondria Huang & Mucke Cell (2012) 5
ApoE4’s Neurotoxicity and Increased Susceptibility to Cleavage Depend on Intramolecular Domain Interaction and Can Be Reduced by “Structure Correctors” Chen et al. JBC 287: 5253–5266 (2012) Mice use spatial cues in the room to locate escape platform hidden under opaque water. 6
Multiple, Stage-Dependent Causes of Cognitive Decline in AD Multiple, Stage-Dependent Causes of Cognitive Decline in AD The Clinical Impact of Cause-specific Treatments The Clinical Impact of Cause-specific Treatments Will Depend on the Relative Impact of the Cause Will Depend on the Relative Impact of the Cause Cause A Cause B Cause A Cause B Alzheimer’s Alzheimer’s Disease Disease Cause C Cause D Cause C Cause D 7
Induced Pluripotent Stem Cells and Biochemical Phenotype of iPS cell-derived Neurons Direct Reprogramming Technologies from Patients with Inherited or Sporadic AD Use human skin or blood cells Use resulting brain cells to study (or treat) to generate human brain cells. Alzheimer’s disease and related conditions. Israel et al. Nature (2012) Examining the Biological Activity of Specific Factors Keck Foundation Program in Brain Cell Engineering (e.g., Human APP/A � � ) in Transgenic Mouse Models � � Steven Finkbeiner and AD Sheng Ding Lots going on here • Lots going on here Subtypes of mature human brain cells Amyloid Plaques and Dystrophic Neurites hAPP FAD #thebrainbot 7 day movie Tg Mouse 8
Studies in Mouse Models of AD Indicate that A � � , Tau and ApoE4 “Conspire” to Cause Neuronal Dysfunction � � Essentially, all models are wrong, but some are useful. Cause A Cause B George Box Alzheimer’s Disease A � � � � ,Tau, Cause D ApoE4 Analyzing Multifactorial Human Diseases in Transgenic Mouse Models Example: Alzheimer’s Disease with Causes A–E (or Z?) Essentially, all models are wrong, but some are useful. Model Phenotype Human Disease George Box A B C D E A � Tau ApoE4 Inflam. Vascular a h o v cc b i p w dd Even Phase II trials in humans often do not reliably predict c j q x ee the outcome of Phase III trials in humans. d k r y ff e l s z gg Mark Geyer f m t aa hh g n u bb ii 9
Analyzing Multifactorial Human Diseases Analyzing Multifactorial Human Diseases in Transgenic Mouse Models in Transgenic Mouse Models Example: Alzheimer’s Disease with Causes A–E (or Z?) Example: Alzheimer’s Disease with Causes A–E (or Z?) Human Disease Human Disease Model Phenotype Model Phenotype A’ A B C D E A’ A B C D E APP/A � A � APP/A � A � Tau ApoE4 Inflam. Vascular Tau ApoE4 Inflam. Vascular a h o v cc a a h o v cc x b i p w dd b i p w dd c j q x ee c c j q x ee d k r y ff d d k r y ff e l s z gg x e l s z gg f m t aa hh f f m t aa hh g n u bb ii g g n u bb ii Analyzing Multifactorial Human Diseases Selection of Molecular Abnormalities that Correlate with in Transgenic Mouse Models Cognitive Deficits in hAPP-J20 Transgenic Mice and Also Occur in Humans with AD Example: Alzheimer’s Disease with Causes A–E (or Z?) Model Phenotype Human Disease Molecule Location Change* Validated in AD A’ A B C D E � ✔ A 2A Receptors Hipp, Astrocytes APP/A � A � Tau ApoE4 Inflam. Vascular � ✔ Calbindin Dentate gyrus Synaptic deficits a a h o v cc � Collagen VI Dentate gyrus ✔ Tau pathology? x b i p w dd � ✔ EphB2 Dentate gyrus Memory problems c c j q x ee � ✔ Neuritic plaques d d k r y ff GIVA-cPLA 2 (AA) Hippocampus Neuronal loss? x e l s z gg � ✔ Klotho Hippocampus Calbindin depletion f f m t aa hh � Metenkephalin Hipp and EC ✔ Nav1.1 depletion g g n u bb ii � ✔ Nav1.1 Parietal Cortex * vs. wildtype controls 10
Developing Better Treatments for AD Developing Better Treatments for AD The Long and Short of It The Long and Short of It Anti-apoE4 drugs A 2A antagonists Klotho boosters Anti-epileptics Aging is the best established risk factor for Alzheimer’s Aging is the best established risk factor for Alzheimer’s disease (AD). disease (AD). Can factors that extend lifespan and promote healthy Can factors that extend lifespan and promote healthy aging counteract AD-related cognitive deficits? aging counteract AD-related cognitive deficits? Dena Dubal, Ph.D. Assistant Professor of Neurology, UCSF Dubal et al. Cell Reports (2014) J. Neurosci. (2015) 11
Klotho Is Depleted in the Hippocampus of Klotho: Suppressor of Aging hAPP-J20 Mice and of Humans with AD • Mutation accelerates aging NTG hAPP Klotho • Over-expression extends Actin lifespan * Ctl AD AD * • High expression in choroid plexus and kidney Klotho Gapdh • Klotho variation in humans modulates longevity and incidence of age-related disease Klotho mutant: short lifespan, pulmonary emphysema, arteriosclerosis, osteoporosis, hypokinesis Kuro-0 1997 Nature Klotho Elevation Enhances Synaptic Plasticity in Mice With or Without hAPP (LTP in Dentate Gyrus) Breeding Scheme and Cerebral Klotho Levels Klotho hAPP/Klotho 12
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