Alzheimer’s Disease and Cholesterol 상무병원 신경과 손의주

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.

Normal Brain

Brain of definite AD

Silver stain, neurofibrillary tangles in AD hippocampus

Silver stain, amyloid plaques in AD cortex

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

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

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

Presenilin-1 mutations in familial AD

Presenilin-2 mutations in familial AD

ApoE4, a genetic risk factor for sporadic AD ApoE 2 1---cys---cys---299 ApoE 3 1---cys---arg---299 ApoE 4 1---arg---arg---299 112 158

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

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

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

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

Recent studies about AD and cholesterol Midlife vascular risk factors and late-life mild cognitive impairment. (Neurology 2001;56:1683-1689) Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model. (Neurobiol Dis 2000;7:321-331) Decreased prevalence of Alzheimer’s disease associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. (Arch Neurol 2000;57:1439-1443)

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

Cholesterol metabolism in peripheral cells

De novo synthesis of cholesterol

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

Cholesterol metabolism within the brain

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)

Net cholsterol flux among neurons and glial cells

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.

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

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)

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

Amyloidogenesis within lipid rafts

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

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

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