The Public Lecture Rudolph E. Tanzi, Ph.D. Joseph P. and Rose F. - - PowerPoint PPT Presentation

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The Public Lecture Rudolph E. Tanzi, Ph.D. Joseph P. and Rose F. - - PowerPoint PPT Presentation

Nov 29, 2022 472 likes •857 views

The Public Lecture Rudolph E. Tanzi, Ph.D. Joseph P. and Rose F. Kennedy Professor of Neurology Vice-Chair, Dept. of Neurology Genetics and Aging Research Unit MassGeneral Institute for Neurodegenerative Disease Massachusetts General Hospital

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The Public Lecture

Rudolph E. Tanzi, Ph.D.

Joseph P. and Rose F. Kennedy Professor of Neurology Vice-Chair, Dept. of Neurology

Genetics and Aging Research Unit MassGeneral Institute for Neurodegenerative Disease Massachusetts General Hospital Harvard Medical School

Rudolph Tanzi, PhD, 2014

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Rudolph Tanzi, PhD, 2014

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Public Speaking: What is it Good For ??

  • Educational Outreach:

Public, Students, Foundations, Associations

  • Fund-Raising: Philanthropic Donors, Private

Foundations, Industry

  • Community Service: Non-profits and Gov. Agencies
  • Public Awareness: Capital Hill, Media, AAAS, NIH

Rudolph Tanzi, PhD, 2014

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Rudolph Tanzi, PhD, 2014

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Public Speaking: Tips for Success

  • Begin and end with a “thank you”; they are there for you!
  • Breath..and choose 4-6 people for eye contact
  • Keep it Simple: Try to explain your research to your uncle
  • Remember: you want to be there..for audience (not yourself)
  • Try to keep it interactive - invite questions throughout talk
  • Avoid Jargon: Say “Nerve Cell” instead of “Neuron”
  • Slide Headings should be like headlines – tell a story
  • The Success Formula:
  • Describe the Problem - Clarity is vital!
  • Create the need for a solution
  • Explain how you are seeking a solution
  • Try to tell personal stories about your research
  • Acknowledge scientists in audience and their contributions
  • Stay calm, cool, and happy during the Q&A (no matter what!)

Rudolph Tanzi, PhD, 2014

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Taking Control of Alzheimer's Through Research Rudolph E. Tanzi, Ph.D.

Chair, Cure Alzheimer’s Fund Research Consortium Joseph P. and Rose F. Kennedy Professor of Neurology Vice-Chair, Dept. of Neurology

Genetics and Aging Research Unit MassGeneral Institute for Neurodegenerative Disease Massachusetts General Hospital Harvard Medical School

Rudolph Tanzi, PhD, 2014

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Alzheimer’s Disease

  • Most common form of dementia in the elderly
  • Brain pathology of Alzheimer’s begins in almost everyone after 40 yrs old
  • Risk Factors:

– Age:

  • 1/5 persons over 65 will get Alzheimer’s
  • Up to 50% over age 85 have AD

– Family History:

  • Strong genetic component (inheritance) involved almost all cases

– Other:

  • Gender: Females > Males
  • Traumatic Brain Injury
  • Stroke, Obesity, High Cholesterol, Diabetes
  • Social Isolation (Loneliness)
  • Depression
  • Emotional trauma, e.g. death of a spouse

Rudolph Tanzi, PhD, 2014

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5.4 million victims in the USA 3.5 million deaths from Alzheimer’s in USA in past 10 years >13 million family members impacted >15 million unpaid caregivers Approximately 40,000,000 worldwide have Alzheimer’s … >>100,000,000+ by 2040

Date source: Alzheimer’s Disease International

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The Disastrous Impact of Alzheimer’s

Rudolph Tanzi, PhD, 2014

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Alzheimer’s could bankrupt the US healthcare budget between 2015 & 2020 if a cure is not found

  • 200

400 600 800 1,000 1,200 1,400 1,600 2010 2015 2020 2025 2030

Medicare/Medicaid Costs per year (billions of dollars)

Tipping Point

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Rudolph Tanzi, PhD, 2014

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2000-2010: Mortality Rates Decreased for Most Major Diseases Except Alzheimer’s

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Rudolph Tanzi, PhD, 2014

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  • Currently, no therapeutics are available to stop the progression of AD
  • FDA-approved AD drugs modestly alleviate symptoms.. temporarily.
  • Acetylcholinesterase inhibitors: Aricept, Exelon, Reminyl
  • NMDA glutamate receptor antagonist: Namenda

Current Therapeutics for Alzheimer’s

×

Rudolph Tanzi, PhD, 2014

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Reducing risk for Alzheimer’s disease now

  • Physical exercise
  • At least a brisk walk everyday
  • Healthy diet
  • Mediterranean diet: Fruits/veggies, olive oil, less red meat
  • Social engagement
  • Hang out with friends
  • Learn new things
  • Attend more lectures
  • Reduce emotional stress
  • Meditation, Yoga
  • Get eight hours of sleep per night
  • Deep sleep consolidates memory: System back-up
  • Deep sleep clears protein debris from brain: Mental floss

Rudolph Tanzi, PhD, 2014

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Rudolph Tanzi, PhD, 2014

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Rudolph Tanzi, PhD, 2014

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Alzheimer’s Disease:

Catastrophic impairment of cognition (memory, learning, reasoning, judgment) to the point that everyday activities and quality

  • f life are severely impacted.

Rudolph Tanzi, PhD, 2014

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1906: Dr. Alois Alzheimer found his patient, Auguste D, 55 yrs old, sitting on a bed with a helpless expression. “What is your name?” he asked. “Auguste,” she replied. “Last name?” “Auguste.” “What is your husband’s name?” “Auguste, I think.” “How long have you been here?” “Three weeks.” (It was her second day in the hospital.) “I have lost myself,” she told her doctor.

Rudolph Tanzi, PhD, 2014

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The Stages of Alzheimer’s Disease

(Science Version)

Rudolph Tanzi, PhD, 2014

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The Evolution of Memory

(Based on the Triune Brain Model)

Brainstem Limbic Neocortex

No need for Acquired Memory Acquired Memory Acquired Memory

  • f Pain/Pleasure
  • f experiences

Instinctive “Self” Emotional “Self” Intellectual “Self” Innate Memory Short-term Long-term Memory Memory

Rudolph Tanzi, PhD, 2014

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Hit disease as early as possible! AD Genes show the way!

Early Prediction

Early Prediction Early Prevention Early Detection

Ending Alzheimer’s: How Do We Use Genes?

Rudolph Tanzi, PhD, 2014

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Milestones in Genetics

Rudolph Tanzi, PhD, 2014

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Original Four AD Genes

Onset Gene Pathogenic Variant Biochemical Phenotype Early Onset <60 yr APP PSEN1 PSEN2 Fully Penetrant Mutations: 24 (+Duplic) 184 15 ↑ Ratio of Aβ42:Aβ40 ↑ Aggregation of Aβ ↑ Production of Aβ Late Onset >60 yr APOE Susceptibilty Factor: ε4 - (3.7 to >10-fold) ↓ Aβ Clearance

(Science version)

Rudolph Tanzi, PhD, 2014

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1987 - 1995 Genetic Disease Defects in 4 Genes

APP PSEN1 PSEN2 APOE

1906 - 1986 Generic Disease Brain Pathology

Amyloid Plaques Tangles

Ending Alzheimer’s: Starts with the Genes

Inflammation

Rudolph Tanzi, PhD, 2014

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Gene Defects

Ending Alzheimer’s: What Do We Learn from AD Genes?

Drug Targets Therapeutic Intervention

APP PSEN1 PSEN2 APOE

Rudolph Tanzi, PhD, 2014

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HIGH CHOLESTEROL HEART DISEASE:

Example: Target for Intervention

Diet, Exercise, Weight Control, Statins, e.g. Lipitor, Crestor

Rudolph Tanzi, PhD, 2014

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ALZHEIMER’S DISEASE: A-Beta

Ending Alzheimer’s: Earliest Drug Target is A-Beta

Diet, Exercise, Weight Control, Drugs?

Rudolph Tanzi, PhD, 2014

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Ab42 a-secretase

Ab

APP

b-secretase

-secretase Ab40 Ab42 Ab40

Cu,Zn

Ab42 Ab

B B B

NFT, Synaptic Dysfunction Reactive microglia Inflammation Early-Stage Intervention

  • Inhibit Ab generation

(GSM, BSI –AZ, Novartis, Roche, Merck, Eisai Early-Stage Intervention

  • Clear Ab from brain

(PBT2; Sola, Gant, Cren) Mid-Stage Intervention

  • Prevent tau tangles

(Rember) Mid-Stage Intervention

  • Neuroprotection

(Growth factors) Late-stage Intervention

  • Anti-inflammatory

(CD33 inhibitors) NP Neuronal Cell Death b-amyloid (Cu-mediated)

(Science version)

Rudolph Tanzi, PhD, 2014

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Tangle Pathology (MID-STAGE) Inflammation (LATE-STAGE)

b-Amyloid Pathology (EARLY-STAGE)

Alzheimer’s Disease Pathology

Rudolph Tanzi, PhD, 2014

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Phase 1: Genome Wide Association Studies

(Completed)

Phase 2: Whole Genome Sequencing

(Ongoing)

Alzheimer’s Genome Project

  • Determine functional roles of new AD genes
  • Find functional variants in AD genes

Phase 3: Functional Studies of New AD Genes

(Ongoing)

  • Identify new AD genes

Model Systems Novel Therapeutics

Cure Alzheimer’s Fund

Rudolph Tanzi, PhD, 2014

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CD33 BIN1 PTK2B CLU ABCA7 CR1

PICALM

MS4A6A CD2AP HLA-DRB1/5 SORL1 SLC24A4 DSG2 INPP5D MEF2C NME8 ZCWPW1 CELF1 FERMT2 EPHA1 CASS4 TREM2 ZNF3 IGHV1-67 TP53INP1 HLA-DRA HS3ST1 SQSTM1 TREML2 NDUFAF6 ECHDC3 AP2A2 ADAMST20 IGH@ SPPL2A TRIP4 SCIMP 14Q Locus DLGAP1 ADAM10 ATXN1

Genome Wide Significant (22) Genome Wide Highly Suggestive (19)

Rudolph Tanzi, PhD, 2014

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  • ~3,000,000 variants/genome
  • A variant every ~1000 bp
  • Total: 51,000,000 DNA

variants!

Rudolph Tanzi, PhD, 2014

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Ab42

a-secretase

Ab

APP

b-secretase

-secretase

Ab40 Ab42 Ab40 Cu,Zn Ab42 Ab B B B

Tangles (Spreading) Reactive microglia Inflammation NP Neuronal Cell Death b-amyloid deposition

Ab production Ab aggregation APP PSEN1 PSEN2 APOE ATXN1 PICALM SORL1 ADAM10 MAPT GRN CHMP2B VCP BIN1 SQSTM1 APOE CR1 CD33 TREM2 TREM2L MS4A6E EPHA1 HLA-DRB INPP5D IGH

Ab production/aggregation Tangles Inflammation

(Science version)

Rudolph Tanzi, PhD, 2014

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APOE CD33 CR1 MAPT GRN CHMP2B VCP BIN1 SQSTM1 MS4A6E EPHA1 TREM2 HLA-DRB INPP5D IGH APP PSEN1 PSEN2 APOE ATXN1 PICALM SORL1 ADAM10

Tangle Pathology (MID-STAGE) Inflammation (LATE-STAGE)

b-Amyloid Pathology (EARLY-STAGE)

Rudolph Tanzi, PhD, 2014

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To end Alzheimer’s we will need a cocktail that will stop b-amyloid, tangles, and inflammation

Rudolph Tanzi, PhD, 2014

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Rudolph Tanzi, PhD, 2014

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Public Speaking: Tips for Success

  • Begin and end with a “thank you”; they are there for you!
  • Breath..and choose 4-6 people for eye contact
  • Keep it Simple: Try to explain your research to your uncle
  • Remember: you want to be there..for audience (not yourself)
  • Try to keep it interactive - invite questions throughout talk
  • Avoid Jargon: Say “Nerve Cell” instead of “Neuron”
  • Slide Headings should be like headlines – tell a story
  • The Success Formula:
  • Describe the Problem - Clarity is vital!
  • Create the need for a solution
  • Explain how you are seeking a solution
  • Try to tell personal stories about your research
  • Acknowledge scientists in audience and their contributions
  • Stay calm, cool, and happy during the Q&A (no matter what!)

Rudolph Tanzi, PhD, 2014

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Rudolph Tanzi, PhD, 2014

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Am I using my brain,

  • r,

Is my brain using me?

Rudolph Tanzi, PhD, 2014