Importance of Cholesterol Metabolism in the Pathology of Alzheimers Disease

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Importance of Cholesterol Metabolism in the
Pathology of Alzheimers Disease

• Alexis Carter
• August 15, 2008
• Principle Investigators Radosveta Koldamova
  Iliya Lefterov

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1. Tangles
A Alzheimers brain

• Pathological characteristics of Alzheimers
  Disease
• Clinically, Alzheimers Diseaseis characterized
  by cognitive decline and memory deficits.

2. Amyloid b Plaques
B Normal brain
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Alzheimers Disease AD

• Most common form of senile dementia
• Probability of AD doubles every 5 years after age
  65
• 5.2 Million people in the United States with AD
• Sixth leading cause of death in the United States
• These facts and figures were produced by The
  Alzheimers Association

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(No Transcript)
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Two Hypotheses

• Amyloid Hypothesis
• Increased formation of Amyloid-ß aggregates?
  neural loss cognitive dysfunction
• Tau Hypothesis
• Negatively regulate the binding to microtubules ?
  forms AD neurofibrillary tangles ? neural loss
  cognitive dysfunction

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Abca1 and Cholesterol Metabolism

• Abca1 is expressed in the brain
• Abca1 is a key player in ApoE lipidation in the
  brain
• Cholesterol binds to lipid-poor ApoA-I and ApoE
  to form HDL
• Lack of Abca1 decreases ApoE and ApoA-I in the
  brain
• Total absence of Abca1 promotes the production of
  amyloid plaques.

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APOA, APOE, Cholesterol and AD

• ApoE
• ApoE2-May have some protection against AD.
• ApoE3-Neither protected nor more likely to
  develop AD.
• ApoE4-More likely to develop AD than others.
• ApoA-I
• Role in AD not well studied.
• Experiments have shown ApoA-I binding to Aß
  decreases aggregation and toxicity.

Cholesterol metabolism, apolipoprotein E,
adenosine triphosphate-binding cassette
transporters, and Alzheimers disease -Vernoica
Hirsh-Reinshagen and Cheryl L. Wellington
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Mouse Model

• APPsw/PS1
• (Amyloid Precursor Protein/Presenilin)
• Transgenic mouse line expressing mutated human
  APP and PS1 genes
• Abca1-/-
• Abca1 knockout mouse with targeted deletion of
  mouse Abca1 gene

http//in.ibtimes.com/data/articlethumbs/1041.jpg
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Hypothesis For Behavioral Testing and MWM

• Abca1 plays a significant role in both cognitive
  and behavioral aspects of AD.
• APP/KO have more Amyloid aggregates in the brain.

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Morris Water Maze
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Abca1 Deficiency Affects Performance in MWM

• Acquisition Phase
• APP/wt versus APP/ko p lt 0.05
• wt/wt versus wt/ko N.S.

• Acquisition Time
• APP/wt versus APP/koplt0.05
• wt/wt versuswt/ko N.S.

• Acquisition Phase
• APP/wt versus APP/ko plt0.05
• wt/wt versus wt/ko N.S.

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Abca1 Deficiency Affects Performance in MWM
(CONT.)
Probe Trial APP/ko crossed the platform
approximately 50 less than APP/wt
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Brain Samples of APP/PS Mice 6 Months Old
APP/wt
APP/ko
198
APP FL
98
68
Ab12-mer Aß
49
38
28
17
14
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Abmonomer
5 6 7 15 16 17
3

• Lack of Abca1 does not affect Ab (Ab 12-mer)

• Lack of Abca1 increases Ab oligomers

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CONCLUSION

• Lack of Abca1 aggravates the memory deficit in
  APP transgenic mice
• Lack of Abca1 increases Aß aggregates in the
  brain and this correlates to memory deficits

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REFLECTION
Department of Environmental and Occupational
Health Radosveta Koldamova M.D/Ph.D Iliya
Lefterov M.D/Ph.D Andy Cronican Ph.D Nicholas
Fitz Ph.D Mitchell Thompson
Thank you!!!