1. Alzheimer’s Disease and Cholesterol
상무병원 신경과
손의주

2. A Characteristic Disease of the Cerebral Cortex
AD Discovery, 1907
Dr. Alois Alzheimer
A Characteristic Disease of the Cerebral Cortex
Case Report:
51 y.o. woman with a five year history of cognitive decline. The patient exhibited increasing memory loss, disorientation, apathy, and incontinence. At autopsy he discovered amyloid plaques, neurofibrillary tangles, and significant neuronal loss.

3. Normal Brain

4. Brain of definite AD

5. Silver stain, neurofibrillary tangles in AD hippocampus

6. Silver stain, amyloid plaques in AD cortex

7. Review of Processing of Amyloid Precursor Protein (APP)Ab
NH2
CO2H Ab
g-secretase
b-secretase
a-secretase p3
g-secretase

8. Classification of AD Familial Alzheimer’s disease A. Early-onset FAD
1. APP on chromosome 21
2. Presenilin 1 on chromosome 14
3. Presenilin 2 on chromosome 1
4. Other unknown mutations – about 50%
B. Late-onset FAD
Sporadic Alzheimer’s disease
ApoE4 – a genetic risk factor

9. APP mutations in familial AD
(FAD) and
familial cerebral amyloidosis

10. Presenilin-1 mutations in familial AD

11. Presenilin-2 mutations in familial AD

12. ApoE4, a genetic risk factor for sporadic AD
ApoE cys---cys---299
ApoE cys---arg---299
ApoE arg---arg---299

13. Pathogenesis of AD APP PS-1, 2 APOE4 accumulation of stable amyloid
neuritic plaque
neurochemical deficit that disrupt cell-to-cell comunication, abnormal synthesis and accumulation of cytoskeletal proteins(e.g., tau), loss of synapses, pruning of dendrites, damage through oxidative metabolism
neuron death and neurotransmitter (Ach) deficit

14. Risk factors for AD Age ApoE4 Family history of AD
Down’s syndrome (chromosome 21)
Low education
Head injury
Female gender

15. Phamachologic treatment of AD
Acetylcholinesterase inhibitor
Aricept, Exelon, Reminyl
Vitamin E

16. Topics to be discussed Recent studies about AD and cholesterol
Cholesterol metabolism in peripheral cells
Cholesterol metabolism within the brain
Synaptic plasma membrane lipid domains
Cholesterol and amyloidogenesis
Cholesterol and ApoE

17. Recent studies about AD and cholesterol
Midlife vascular risk factors and late-life mild cognitive impairment.
(Neurology 2001;56: )
Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model.
(Neurobiol Dis 2000;7: )
Decreased prevalence of Alzheimer’s disease associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.
(Arch Neurol 2000;57: )

18. Decreased prevalence of Alzheimer’s disease associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

19. Cholesterol metabolism in peripheral cells

20. De novo synthesis of cholesterol

21. Four mechanisms to keep cholesterol levels constant
LDL uptake
De novo synthesis
Cholesterol esterification
HDL efflux

22. Cholesterol metabolism within the brain

23. Net cholesterol flux across the brain
Essentially all cholesterol input into the CNS come from de novo synthesis
ApoE extract intracellular cholesterol and form ApoE:lipid complexes
24- hydroxylase convert cholesterol to 24S-hydroxycholesterol, a hydrophilic compound that crosses the BBB (40% of cholesterol output from the CNS)

24. Net cholsterol flux among neurons and glial cells

25. Two key questions about the cholesterol metabolism within the brain
What process signals the increase in cholesterol intake and the rise the plasma cholesterol concentration to the CNS.
Whether or not there is also a role for other proteins such as SR-B1, ABCA1 or ABCB4 in cholesterol secretary process.

28. Potential candidates regulating SPM cholesterol asymmetry
ApoE (apolipoprotein E)
1. ApoE is synthesized in astrocytes and transported to neurons.
2. While the amount of ApoE is increased with age, its function could be impaired.
LDLR (low density-lipoprotein receptor)
SCP-2 (sterol carrier protein-2)
Polyunsaturated fatty acid
Fatty acid binding protein

30. Lipid rafts 구성 1. Cholesterol
2. Sphingolipids (sphingomyelin, gangliosides)
3. Glycosylphophatidylinositol (GPI) proteins
위치 : exofacial leaflet 기능
1. sorting of different molecules
2. protein activity
3. cell signaling
4. regulation of transbilayer distribution of cholesterol (potential role)

31. Lipid rafts – Two possibilities
Amyloidogenic processing of APP occurs within rafts, whereas nonamyloidogenic cleavage takes place outside rafts
If lipid rafts are localized in the exofacial leaflet then certainly increasing the amount of cholesterol in the exofacial leaflet that was observed in aged animals would have an impact on both the structure and function of lipid rafts

32. Amyloidogenesis within lipid rafts

33. The possible role of ApoE4 in Alzheimer’s disease
Increased Abeta fibrillogenesis
Decreased Abeta clearance
Decreased neuronal repair
Less efficient cholesterol efflux from neurons causing higher cholesterol levels that would allow more Abeta to be produced

34. Risk factors for AD Age ApoE4 Family history of AD
Down’s syndrome (chromosome 21)
Low education
Head injury
Female gender
High cholesterol (?)
Hypertension (?)

35. Phamachologic treatment of AD
Acetylcholinesterase inhibitor
Aricept, Exelon, Reminyl
Vitamin E
Statins (?)