Alzheimer's Disease and Frontotemporal Dementias

A Review with Particular Reference to Pin1 Protein

 

Home

Pin1 Protein

Our Research

Our TEM Research

Our Publications

Research Team

Alzheimer's Disease

Tauopathies

About this Site

Literature:   A-K ; L-Z ; subject area

Search Site by Subject Area

Disclaimer/ Feedback

Links

Compiled by: Julian Thorpe

 

Apolipoprotein E

Please Note: Due to time constraints, the text part of this page has not been updated for some time. However, references are added reasonably frequently.

ApoE in relation to: apoptosis ; beta-amyloid ; cytoskeleton ; oxidative stress ; references

General

Apolipoprotein E (apoE) is a normal constituent of cells which is involved in lipid movement both within cells and across membranes.

The ApoE gene is located on chromosome 19 and its most common alleles are called e2, e3 and e4 . While this gene does not itself cause AD, its different alleles can alter the relative risk of an individual developing the disease.
ApoE is thus a susceptibility factor which can give rise to a sporadic, late-onset form of AD.
For example, possession of two e 4 alleles can increase the risk of AD some 8-fold. Studies have shown the e4 allele to be associated with decreased longevity, increased cholesterol levels, cardiovascular disease and particularly  AD (see Smith, 2000). It also negatively influences functional recovery following a variety of brain insults (see Saunders, 2000)..
The e2 allele, conversely, apparently confers some protection.
ApoE was discovered as a plasma protein involved in lipoprotein metabolism and is the primary protein component of CNS (central nervous system) lipoproteins.
ApoE is synthesized by the liver and is also made locally in the brain.
ApoE knock-out mice evidenced dendritic alterations which led to synaptic simplification similar to that seen in AD.
In his recent review, Saunders (2000), suggests apoE to be a multifunctional molecule. He lists the potential roles for brain apoE as being in: amyloid deposition and clearance; stability; intracellular signaling; immune modulation; glucose metabolism; and oxidative stress .
And also see the review by Mahley and Rall (2000) .

ApoE and Apoptosis

Hashimoto et al. (2000) haveexamined apoE effects upon neuron/neuroblastoma hybrid F11 and non-neuronal Chinese hamster ovary cells, glioblastomas and SH-SY5Y neuroblastomas. They suggest that apoE4 may have a direct role in AD pathogenesis by activating cell type-specific apoptosis involving LRP and the Gi class of GTPases.
Drouet et al. (2001) have shown that the ApoE2 and E3 isoforms protect cortical neurones against apoptotic cell death induced by a non-fibrillar form of the A beta (1-40), A beta (12-42), A beta (29-40) and A beta (29-42) peptides, whereas apoE4 had no effect.
Back to Top

ApoE and Beta-Amyloid
ApoE protein interacts with both beta-amyloid and tau in an isoform-specific manner (Fleming et al., 1996) .
There is some evidence that apoE may be involved in beta-amyloid plaque production. For example, Ladu et al. (2000) suggest that beta-amyloid associates with lipoproteins in general, and specifically apoE, to enable transport and clearance. They demonstrated that apoE2 and E3formed stable complexes with beta-amyloid(at levels 20-fold greater than that occurring with apoE4) and thatapoE3 (but not E4) prevented the neurotoxic effects of beta-amyloid (mediated by the uptake of these complexes via apoE receptors).
The low-density lipoprotein receptor-related protein (LRP) is the major neuronal receptor both for apoE and alpha2-macroglobulin and also interacts with beta-amyloid. Hyman et al. (2000) have reviewed the data and suggest that LRP plays an important role in beta-amyloid metabolism and hence AD (via clearance of apoE/A beta and alpha2M/A beta complexes).
Bornemann and Staufenbiel (2000) have generated transgenic mouse lines expressing the human amyloid precursor protein (APP). Their model system displayed plaques which had associated apolipoprotein E (and other typical AD pathological features).
Carter et al. (2001) have shown that human ApoE4 accelerates beta-amyloid deposition in APPsw transgenic mouse brain and this has been suggested to be the case in vivo also (Cho et al., 2001).
Drouet et al. (2001) have shown that the ApoE2 and E3 isoforms protect cortical neurones against apoptotic cell death induced by a non-fibrillar form of the A beta (1-40), A beta (12-42), A beta (29-40) and A beta (29-42) peptides, whereas apoE4 had no effect.
Other references on this area of APP/A beta interactions with ApoE include: (Hass et al., 2001; Holtzman, 2001; Morishima-Kawashima et al., 2000; Terai et al., 2001; Yamauchi et al., 2002).
Back to Top

ApoE and the Cytoskeleton
Roses et al. (1996) localised apoE to the neuronal cytoplasm and suggested that apoE3 (and apoE2) prevented PHF formation by interacting with the microtubule binding domain of tau . In this way it also protects the site for microtubule stabilising interactions with beta-tubulin.
Lovestone et al. (2001) have reviewed the evidence for and against an interaction between ApoE and the neuronal cytoskeleton , in particular with the microtubule-associated protein tau
Ljungberg et al. (2002) have shown that truncated apoE forms tangle -like structures in a neuronal cell line
Back to Top

ApoE and Oxidative Stress
ApoE is susceptible to free radicals, but may also act as a free radical scavenger (see Oxidative Stress ).
The e4 allele of ApoE has the poorest anti-oxidant potential (e.g. Ihara et al., 2000).
Gibson et al. (2000) suggest that mitochondrial/oxidative damage may be more important for the cognitive dysfunction in AD patients with the ApoE4 allele.
Cedazo-Minguez and Cowburn (2001) have reviewed the involvement of ApoE in AD, including oxidative stress .
Back to Top

Some Related References

N.B. Free Medical Journals online now at : http://www.freemedicaljournals.com/
(These journals include: Neurology, Neurobiology of Disease, Journal of Neurochemistry, Alzheimer's Disease Review)

Ait-Ghezala, G, Abdullah, L, Crescentini, R, Crawford, F, Town, T, Singh, S, Richards, D, Duara, R, Mullan, M (2002) Confirmation of association between D10S583 and Alzheimer's disease in a case-control sample. NEUROSCIENCE LETTERS 325: 87-90

Bertram, L, Tanzi, RE (2001) Dancing in the dark? The status of late-onset Alzheimer's disease genetics. JOURNAL OF MOLECULAR NEUROSCIENCE 17: 127-136

Bi, XN, Yong, AP, Zhou, J, Ribak, CE and Lynch, G (2001) Rapid induction of intraneuronal neurofibrillary tangles in apolipoprotein E-deficient mice. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 98: 8832-8837

Back to Top

Boccardi, M, Sabattoli, F, Testa, C, Beltramello, A, Soininen, H, Frisoni, GB (2004) APOE and modulation of Alzheimer's and frontotemporal dementia. NEUROSCIENCE LETTERS 356: 167-170

Bornemann, KD and Staufenbiel, M (2000) Transgenic mouse models of Alzheimer's disease. MOLECULAR AND CELLULAR GERONTOLOGY 908: 260-266

Bronfman, FC, Tesseur, I, Hofker, MH, Havekens, LM and Van Leuven, F (2000) No evidence for cholinergic problems in apolipoprotein E knockout and apolipoprotein E4 transgenic mice. NEUROSCIENCE 97: 411-418

Buttini_M, Orth_M, Bellosta_S, Akeefe_H, Pitas_RE, WyssCoray_T, Mucke_L, Mahley_RW. (1999) Expression of human apolipoprotein E3 or E4 in the brains of Apoe(-/-) mice: Isoform-specific effects on neurodegeneration. JOURNAL OF NEUROSCIENCE, 1999, Vol.19, No.12, pp.4867-4880

Carrieri, G, Bonafe, M, De Luca, M, Rose, G, Varcasia, O, Bruni, A, Maletta, R, Nacmias, B, Sorbi, S, Corsonello, F, Feraco, E, Andreev, KF, Yashin, AI, Franceschi, C and De Benedictis, G (2001) Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer's disease. HUMAN GENETICS 108: 194-198

Carter, DB, Dunn, E, McKinley, DD, Stratman, NC, Boyle, TP, Kuiper, SL, Oostveen, JA, Weaver, RJ, Boller, JA, Gurney, ME (2001) Human apolipoprotein E4 accelerates beta-amyloid deposition in APPsw transgenic mouse brain. ANNALS OF NEUROLOGY 50: 468-475

Cataldo, AM, Peterhoff, CM, Troncosco, JC, Gomez-Isla, T, Hyman, BT and Nixon, RA (2000) Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome - Differential effects of APOE genotype and presenilin mutations. American Journal Of Pathology 157: 277-286

Cedazo-Minguez, A, Cowburn, RF (2001) Apolipoprotein E: a major piece in the Alzheimer's disease puzzle. JOURNAL OF CELLULAR AND MOLECULAR MEDICINE 5: 254-266

Back to Top

Cedazo-Minguez, A, Huttinger, M and Cowburn, RF (2001) beta-VLDL protects against A beta(I-42) and apoE toxicity in human SH-SY5Y neuroblastoma cells. NEUROREPORT 12: 201-206

Cedazo-Minguez, A, Popescu, BO, Blanco-Millan, JM, Akterin, S, Pei, JJ, Winblad, B, Cowburn, RF (2003) Apolipoprotein E and beta-amyloid (1-42) regulation of glycogen synthase kinase-3 beta. JOURNAL OF NEUROCHEMISTRY 87: 1152-1164

Cho, HS, Hyman, BT, Greenberg, SM and Rebeck, GW (2001) Quantitation of apoE domains in Alzheimer disease brain suggests a role for apoE in A beta aggregation. JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY 60: 342-349

Combarros, O, Garcia-Roman, M, Fontalba, A, Fernandez-Luna, JL, Llorca, J, Infante, J, Berciano, J (2003) Interaction of the H63D mutation in the hemochromatosis gene with the apolipoprotein E epsilon 4 allele modulates age at onset of Alzheimer's disease. DEMENTIA AND GERIATRIC COGNITIVE DISORDERS 15: 151-154

Daw, EW, Bird, TD, Nemens, EJ, Nochlin, D, Schellenberg, GD and Wijsman, EM (2000) ApoE and other loci affect age of Alzheimer's disease onset in families with PS2 mutation. AMERICAN JOURNAL OF HUMAN GENETICS 67: 192

Dayanandan, R, Ljungberg, MC, Pearce, J, Anderton, BH and Lovestone, S (2000) Monitoring the intracellular fate of apolipoprotein E: Implications for Alzheimer's disease. EUROPEAN JOURNAL OF NEUROSCIENCE 12: 348

Desai, PP, Hendrie, HC, Evans, RM, Murrell, JR, DeKosky, ST, Kamboh, MI (2001) Genetic variation in apolipoprotein D affects the risk of Alzheimer's disease in African Americans. AMERICAN JOURNAL OF HUMAN GENETICS 69: 1370

Desai, PP, Hendrie, HC, Evans, RM, Murrell, JR, DeKosky, ST, Kamboh, MI (2003) Genetic variation in apolipoprotein D affects the risk of Alzheimer disease in African-Americans. AMERICAN JOURNAL OF MEDICAL GENETICS PART B NEUROPSYCHIATRIC GENETICS 116B: 98-101  

Diaz-Cintra, S, Yong, A, Aguilar, A, Bi, XN, Lynch, G, Ribak, CE (2004) Ultrastructural analysis of hippocampal pyramidal neurons from apolipoprotein E-deficient mice treated with a cathepsin inhibitor. JOURNAL OF NEUROCYTOLOGY 33: 37-48

Drake, J, Link, CD, Butterfield, DA (2003) Oxidative stress precedes fibrillar deposition of Alzheimer's disease amyloid beta-peptide (1-42) in a transgenic Caenorhabditis elegans model. NEUROBIOLOGY OF AGING 24: 415-420

Drouet, B, Fifre, A, Pincon-Raymond, M, Vandekerckhove, J, Rosseneu, M, Gueant, JL, Chambaz, J and Pillot, T (2001) ApoE protects cortical neurones against neurotoxicity induced by the non-fibrillar C-terminal domain of the amyloid-beta peptide. JOURNAL OF NEUROCHEMISTRY 76: 117-127

Fagan, AM, Watson, M, Parsadanian, M, Bales, KR, Paul, SM, Holtzman, DM (2002) Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of Alzheimer's disease. NEUROBIOLOGY OF DISEASE 9: 305-318

Fleming_LM, Weisgraber_KH, Strittmatter_WJ, Troncoso_JC, Johnson_GVW. (1996) Differential binding of apolipoprotein E isoforms to tau and other cytoskeletal proteins. EXPERIMENTAL NEUROLOGY, 1996, Vol.138, No.2, pp.252-260

Back to Top

Fullerton, SM, Clark, AG, Weiss, KM, Nickerson, DA, Taylor, SL, Stengard, JH, Salomaa, V, Vartiainen, E, Perola, M, Boerwinkle, E and Sing, CF (2000) Apolipoprotein E variation at the sequence haplotype level: Implications for the origin and maintenance of a major human polymorphism. AMERICAN JOURNAL OF HUMAN GENETICS 67: 881-900

Gibson, GE, Haroutunian, V,  Zhang, H, Park, LCH, Shi, Q, Lesser, M, Mohs, RC, Sheu, RKF and Blass, JP (2000) Mitochondrial damage in Alzheimer's disease varies with apolipoprotein E genotype. ANNALS OF NEUROLOGY 48: 297-303

Gold, G, Blouin, JL, Herrmann, FR, Michon, A, Mulligan, R, Sail, GD, Bouras, C, Giannakopoulos, P, Antonarakis, SE, A-Ntonarakis, SE (2003) Specific BACE1 genotypes provide additional risk for late-onset Alzheimer disease in APOE epsilon 4 carriers. AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS 119B: 44-47

Gomez-Ramos, P, Mufson, EJ, Moran, MA (2001) Apolipoprotein E immunoreactivity in neurons and neurofibrillary degeneration of aged non-demented and Alzheimer's disease patients. MICROSCOPY RESEARCH AND TECHNIQUE 55: 48-58

Harris, FM, Brecht, WJ, Xu, Q, Mahley, RW, Huang, YD (2004) Increased tau phosphorylation in apolipoprotein E4 transgenic mice is associated with activation of extracellular signal-regulated kinase - Modulation by zinc. JOURNAL OF BIOLOGICAL CHEMISTRY 279: 44795-44801

Hartman, RE, Wozniak, DF, Nardi, A, Olney, JW, Sartorius, L and Holtzman, DM (2001) Behavioral phenotyping of GFAP-ApoE3 and-ApoE4 transgenic mice: ApoE4 mice show profound working memory impairments in the absence of Alzheimer's-like neuropathology. EXPERIMENTAL NEUROLOGY 170: 326-344

Hartmann, T (2001) Cholesterol, A beta and Alzheimer's disease. TRENDS IN NEUROSCIENCES 24: S45-S48

Hashimoto, M, Yasuda, M, Tanimukai, S, Matsui, M, Hirono, N, Kazui, H, Mori, E (2001) Apolipoprotein E epsilon 4 and the pattern of regional brain atrophy in Alzheimer's disease. NEUROLOGY 57: 1461-1466

Hashimoto, Y, Jiang, H, Niikura, T, Ito, Y, Hagiwara, A, Umezawa, K, Abe, Y, Murayama, Y and Nishimoto, I (2000) Neuronal apoptosis by apolipoprotein E4 through low-density lipoprotein receptor-related protein and heterotrimeric GTPases. JOURNAL OF NEUROSCIENCE 20: 8401-8409

Back to Top

Hass, S, Weidemann, A, Utermann, G and Baier, G (2001) Intracellular apolipoprotein E affects amyloid precursor protein processing and amyloid A beta production in COS-1 cells. MOLECULAR GENETICS AND GENOMICS 265: 791-800

Holtzman, DM (2001) Role of apoE/A beta interactions in the pathogenesis of Alzheimer's disease and cerebral amyloid angiopathy. JOURNAL OF MOLECULAR NEUROSCIENCE 17: 147-155

Horsburgh, K, McCulloch, J, Nilsen, M, Roses, AD and Nicoll, JAR (2000) Increased neuronal damage and apoE immunoreactivity in human apolipoprotein E, E4 isoform-specific, transgenic mice after global cerebral ischaemia. EUROPEAN JOURNAL OF NEUROSCIENCE 12: 4309-4317

Huang, YD, Liu, XQ, Wyss-Coray, T, Brecht, WJ, Sanan, DA and Mahley, RW (2001) Apolipoprotein E fragments present in Alzheimer's disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 98: 8838-8843

Huang, YD, Weisgraber, KH, Mucke, L, Mahley, RW (2004) Apolipoprotein E. JOURNAL OF MOLECULAR NEUROSCIENCE 23: 189-204

Huber, G, Marz, W, Martin, JR, Malherbe, P, Richards, JG, Sueoka, N, Ohm, T and Hoffmann, MM (2000) Characterization of transgenic mice expressing apolipoprotein E4(C112R) and apolipoprotein E4(L28P; C112R). NEUROSCIENCE 101: 211-218

Hyman BT; Strickland D; Rebeck GW.(2000) Role of the low-density lipoprotein receptor-related protein in beta-amyloid metabolism and Alzheimer disease. Arch Neurol, 2000 May, 57:5, 646-50

Ihara, Y, Hayabara, T, Sasaki, K, Kawada, R, Nakashima, Y and Kuroda, S (2000) Relationship between oxidative stress and apoE phenotype in Alzheimer's disease. ACTA NEUROLOGICA SCANDINAVICA 102: 346-349

Ingelson, M, Fabre, SF, Lilius, L, Andersen, C, Viitanen, M, Almkvist, O, Wahlund, LO and Lannfelt, L (2001) Increased risk for frontotemporal dementia through interaction between tau polymorphisms and apolipoprotein E epsilon 4. NEUROREPORT 12: 905-909

Back to Top

Ki, CS, Na, DL, Kim, DK, Kim, HJ, Kim, JW (2002) Genetic association of an apolipoprotein C-I (APOC1) gene polymorphism with late-onset Alzheimer's disease. NEUROSCIENCE LETTERS 319: 75-78

Kida, E, Choimiura, NH And Wisniewski, KE (1995) Deposition of apolipoprotein-e and apolipoprotein-j in senile plaques is topographically determined in both alzheimers-disease and downs-syndrome brain. BRAIN RESEARCH 685: 211-216

Kim, HC, Kim, DK, Choi, IJ, Kang, KH, Yi, SD, Park, J and Park, YN (2001) Relation of apolipoprotein E polymorphism to clinically diagnosed Alzheimer's disease in the Korean population. PSYCHIATRY AND CLINICAL NEUROSCIENCES 55: 115-120

Kobayashi, M, Ishiguro, K, Katoh-Fukui, Y, Yokoyama, M, Fujita, SC (2003) Phosphorylation state of tau in the hippocampus of apolipoprotein E4 and E3 knock-in mice. NEUROREPORT 14: 699-702

Kontush, A, Berndt, C, Weber, W, Akopyan, V, Arlt, S, Schippling, S and Beisiegel, U (2001) Amyloid-beta is an antioxidant for lipoproteins in cerebrospinal fluid and plasma. FREE RADICAL BIOLOGY AND MEDICINE 30: 119-128

Kwon, JM. Chakraverty, S, Martinez, M, Morris, JC and Goate, AM (2000) The association between low density lipoprotein receptor-related protein (LRP) and Alzheimer's disease is modified by apolipoprotein E and alpha-2 macroglobulin. AMERICAN JOURNAL OF HUMAN GENETICS 67: 1206

Ladu MJ; Reardon C; Van Eldik L; Fagan AM; Bu G; Holtzman D; Getz GS. (2000) Lipoproteins in the central nervous system. Ann N Y Acad Sci, 2000 Apr, 903:, 167-75

Lane, RM, Farlow, MR (2005) Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer's disease. JOURNAL OF LIPID RESEARCH 46: 949-968

Lauderback, CM, Kanski, J, Hackett, JM, Maeda, N, Kindy, MS, Butterfield, DA (2002) Apolipoprotein E modulates Alzheimer's A beta(1-42)-induced oxidative damage to synaptosomes in an allele-specific manner. BRAIN RESEARCH 924: 90-97

Law, A, Gauthier, S and Quirion, R (2001) Say NO to Alzheimer's disease: the putative links between nitric oxide and dementia of the Alzheimer's type. BRAIN RESEARCH REVIEWS 35: 73-96

Back to Top

Ljungberg, MC, Dayanandan, R, Asuni, A, Rupniak, TH, Anderton, BH, Lovestone, S (2002) Truncated apoE forms tangle-like structures in a neuronal cell line. NEUROREPORT 13: 867-870

Lovestone, S, Anderton, B, Betts, J, Dayanadan, R, Gibb, G, Ljungberg, C, Pearce, J (2001) Apolipoprotein E gene and Alzheimer's disease: is tau the link? NEURONAL SIGNAL TRANSDUCTION AND ALZHEIMER'S DISEASE 67: 111-120

Lynch, JR, Morgan, D, Mance, J, Matthew, WD and Laskowitz, DT (2001) Apolipoprotein E modulates glial activation and the endogenous central nervous system inflammatory response. JOURNAL OF NEUROIMMUNOLOGY 114: 107-113

Mahley, RW and Rall, SC (2000) Apolipoprotein E: Far more than a lipid transport protein. ANNUAL REVIEW OF GENOMICS AND HUMAN GENETICS 1: 507-537

Martins, RN, Taddei, K, Kendall, C, Evin, G, Bates, KA, Harvey, AR (2001) Altered expression of apolipoprotein E, amyloid precursor protein and presenilin-1 is associated with chronic reactive gliosis in rat cortical tissue. NEUROSCIENCE 106: 557-569

Matsubara-Tsutsui, M, Yamagata, H, Morishima, A, Nakura, J, Mitsuda, N, Kamino, K, Kondo, I, Miki, T (2002) The-4,752 C/T polymorphism in the presenilin 1 gene increases the risk of Alzheimer's disease in apolipoprotein E4 carriers . INTERNAL MEDICINE 41: 823-828

Morishima-Kawashima, M, Oshima, N, Ogata, H, Yamaguchi, H, Yoshimura, M, Sugihara, S and Ihara, Y (2000) Effect of apolipoprotein E allele epsilon 4 on the initial phase of amyloid beta-protein accumulation in the human brain. AMERICAN JOURNAL OF PATHOLOGY 157: 2093-2099

Munson, GW, Roher, AE, Kuo, YM, Gilligan, SM, Reardon, CA, Getz, GS and LaDu, MJ (2000) SDS-stable complex formation between native apolipoprotein E3 and beta-amyloid peptides. BIOCHEMISTRY 39: 16119-16124

Naidu, A, Catalano, R, Bales, K, Wu, S, Paul, SM and Cordell, B (2001) Conversion of brain apolipoprotein E to an insoluble form in a mouse model of Alzheimer disease. NEUROREPORT 12: 1265-1270

Back to Top

Nakamura, S, Ono, F, Hamano, M, Odagiri, K, Kubo, M, Komatsuzaki, K, Terao, K, Shinagawa, M, Takahashi, K and Yoshikawa, Y (2000) Immunohistochemical detection of apolipoprotein E within prion-associated lesions in squirrel monkey brains. ACTA NEUROPATHOLOGICA 100: 365-370

Nagy, Z (2000b) Cell cycle regulatory failure in neurones: causes and consequences. NEUROBIOLOGY OF AGING 21: 761-769

Neely, MD, Swift, LL and Montine, TJ (2000) Human, but not bovine, oxidized cerebral spinal fluid lipoproteins disrupt neuronal microtubules. LIPIDS 35: 1249-1257

Nixon, RA, Cataldo, AM and Mathews, PM (2000) The endosomal-lysosomal system of neurons in Alzheimer's disease pathogenesis: A review. NEUROCHEMICAL RESEARCH 25: 1161-1172

Ohkubo, N, Lee, YD, Morishima, A, Terashima, T, Kikkawa, S, Tohyama, M, Sakanaka, M, Tanaka, J, Maeda, N, Vitek, MP, Mitsuda, N (2002) Apolipoprotein E and Reelin ligands modulate tau phosphorylation through an Apolipoprotein E receptor/disabled-1/glycogen synthase kinase-3 beta cascade. FASEB JOURNAL 16: U567-U586

Ohkubo, N, Mitsuda, N, Tamatani, M, Yamaguchi, A, Lee, YD, Ogihara, T, Vitek, MP and Tohyama, M (2001) Apolipoprotein E4 stimulates cAMP response element-binding protein transcriptional activity through the extracellular signal-regulated kinase pathway. JOURNAL OF BIOLOGICAL CHEMISTRY 276: 3046-3053

Ohm, TG, Hamker, U, Cedazo-Minguez, A, Rockl, W, Scharnagl, H, Marz, W, Cowburn, R, Muller, W, Meske, V (2001) Apolipoprotein E and beta A4-amyloid: signals and effects. NEURONAL SIGNAL TRANSDUCTION AND ALZHEIMER'S DISEASE 67: 121-129

Panza, F, Colacicco, AM, Basile, AM, Capurso, C, D'Introno, A, Mastroianni, F, Scicutella, G, Capurso, A and Solfrizzi, V (2001) Impact of decreased frequency of apolipoprotein E epsilon 4 allele on Alzheimer's disease in Southern Italy. ARCHIVES OF GERONTOLOGY AND GERIATRICS 7: 299-306

Pericak-Vance, MA, Grubber, J, Bailey, LR, Hedges, D, West, S, Santoro, L, Kemmerer, B, Hall, JL, Saunders, AM, Roses, AD, Small, GW, Scott, WK, Conneally, PM, Vance, JM and Haines, JL (2000) Identification of novel genes in late-onset Alzheimer's disease. EXPERIMENTAL GERONTOLOGY 35: 1343-1352

Back to Top

Peila, R, Rodriguez, BL, Launer, LJ (2002) Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies - The Honolulu-Asia Aging Study. DIABETES 51: 1256-1262

Poeggeler, B, Miravalle, L, Zagorski, MG, Wisniewski, T, Chyan, YJ, Zhang, YB, Shao, HY, Bryant-Thomas, T, Vidal, R, Frangione, B, Ghiso, J, Pappolla, MA (2001) Melatonin reverses the profibrillogenic activity of apolipoprotein E4 on the Alzheimer amyloid A beta peptide. BIOCHEMISTRY 40: 14995-15001

Poirier, J (2000) Apolipoprotein E and Alzheimer's disease - A role in amyloid catabolism. ANNALS OF THE NEW YORK ACADEMY OF SCIENCES. ALZEHEIMER'S DISEASE: A COMPENDIUM OF CURRENT THEORIES 924: 81-90

Raber, J, Huang, YD, Ashford, JW (2004) ApoE genotype accounts for the vast majority of AD risk and AD pathology. NEUROBIOLOGY OF AGING 25: 641-650

Ramassamy, C, Krzywkowski, P, Averill, D, Lussier-Cacan, S, Theroux, L, Christen, Y, Davignon, J and Poirier, J (2001) Impact of apoE deficiency on oxidative insults and antioxidant  levels in the brain. MOLECULAR BRAIN RESEARCH 86: 76-83

Rassart, E, Bedirian, A, Do Carmo, S, Guinard, O, Sirois, J, Terrisse, L and Milne, R (2000) Apolipoprotein D. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEIN STRUCTURE AND MOLECULAR ENZYMOLOGY 1482: 185-198

Retz, W, Thome, J, Durany, N, Harsanyi, A, Retz-Junginger, P, Kornhuber, J, Riederer, P, Rosler (2001) Potential genetic markers of sporadic Alzheimer's dementia. PSYCHIATRIC GENETICS 11: 115-122

Richard, F and Amouyel, P (2001) Genetic susceptibility factors for Alzheimer's disease. EUROPEAN JOURNAL OF PHARMACOLOGY 412: 1-12

Roses_AD, Einstein_G, Gilbert_J, Goedert_M, Han_SH, Huang_D, Hulette_C, Masliah_E, PericakVance_MA, Saunders_AM,  Schmechel_DE, Strittmatter_WJ, Weisgraber_KH, Xi_PT. (1996) Morphological, biochemical, and genetic support for an  apolipoprotein E effect on microtubular metabolism. ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, 1996, Vol.777, pp.146-157

Back to Top

Sabo, T, Lomnitski, L, Nyska, A, Beni, S, Maronpot, RR, Shohami, E, Roses, AD and Michaelson, DM (2000)  Susceptibility of transgenic mice expressing human apolipoprotein E to closed head injury: The allele E3 is neuroprotective whereas E4 increases fatalities. NEUROSCIENCE 101: 879-884

Sanchez, L, Alvarez, V, Gonzalez, P, Gonzalez, I, Alvarez, R and Coto, E (2001) Variation in the LRP-associated protein gene (LRPAP1) is associated with late-onset Alzheimer disease. AMERICAN JOURNAL OF MEDICAL GENETICS 105: 76-78

Saunders, AM (2000) Apolipoprotein E and Alzheimer disease: An update on genetic and functional analyses. JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY 59: 751-758

Shibata, M, Yamada, S, Kumar, SR, Calero, M, Bading, J, Frangione, B, Holtzman, DM, Miller, CA, Strickland, DK, Ghiso, J and Zlokovic, BV (2000) Clearance of Alzheimer's amyloid-beta(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. JOURNAL OF CLINICAL INVESTIGATION 106: 1489-1499

Siest, G, Bertrand, P, Herbeth, B, Vincent-Viry, M, Schiele, F, Sass, C and Visvikis, S (2000) Apolipoprotein E polymorphisms and concentration in chronic diseases and drug responses. CLINICAL CHEMISTRY AND LABORATORY MEDICINE 38: 841-852

Smith JD. (2000) Apolipoprotein E4: an allele associated with many diseases. Ann Med, 2000 Mar, 32:2, 118-27

Stevens, I, Van Osta, P, Geerts, H, Verheyen, G, Van Hauwaert, ML, Cras, P, Engelborghs, S, De Deyn, PP, Martin, JJ, Van Broeckhoven, C and Moens, L (1998) Processing of apolipoprotein E in cerebrospinal fluid of patients with Alzheimer's disease. ALZHEIMERS REPORTS 1: 257-265

Back to Top

St George-Hyslop, PH (2000) Genetic factors in the genesis of Alzheimer's disease. ANNALS OF THE NEW YORK ACADEMY OF SCIENCES. ALZEHEIMER'S DISEASE: A COMPENDIUM OF CURRENT THEORIES 924: 1-7

Strittmatter, WJ (2000) Apolipoprotein E and Alzheimer's disease. ANNALS OF THE NEW YORK ACADEMY OF SCIENCES. ALZEHEIMER'S DISEASE: A COMPENDIUM OF CURRENT THEORIES 924: 91-92

Strittmatter, WJ (2001) Apolipoprotein E and Alzheimer's disease: signal transduction mechanisms. NEURONAL SIGNAL TRANSDUCTION AND ALZHEIMER'S DISEASE 67: 101-109

Terai, K, Iwai, A, Kawabata, S, Sasamata, M, Miyata, K and Yamaguchi, T (2001) Apolipoprotein E deposition and astrogliosis are associated with maturation of beta-amyloid plaques in beta APPswe transgenic mouse: Implications for the pathogenesis of Alzheimer's disease. BRAIN RESEARCH 900: 48-56

Tesseur, I, Van Dorpe, J, Bruynseels, K, Bronfman, F, Sciot, R, Van Lommel, A and Van Leuven, F (2000) Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord. AMERICAN JOURNAL OF PATHOLOGY 157: 1495-1510

Tesseur, I, Van Dorpe, J, Spittaels, K, Van den Haute, C, Moechars, D and Van Leuven, F (2000) Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice. AMERICAN JOURNAL OF PATHOLOGY 156: 951-964

Teter, B (2000) Apolipoprotein E isotype-specific effects in neurodegeneration. ALZHEIMERS REPORTS 3: 199-212

Thaker, U, McDonagh, AM, Iwatsubo, T, Lendon, CL, Pickering-Brown, SM, Mann, DMA (2003) Tau load is associated with apolipoprotein E genotype and the amount of amyloid beta protein, A beta(40), in sporadic and familial Alzheimer's disease. NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY 29: 35-44

Togo, T, Cookson, N, Dickson, DW (2002) Argyrophilic grain disease: Neuropathology, frequency in a dementia brain bank and lack of relationship with apolipoprotein E. BRAIN PATHOLOGY 12: 45-52

Tsuboi, Y, Josephs, KA, Cookson, N, Dickson, DW (2003) APOE E4 is a determinant for Alzheimer type pathology in progressive supranuclear palsy. NEUROLOGY 60: 240-245

Back to Top

Umans, L, Serneels, L, Lorent, K, Dewachter, I, Tesseur, I, Moechars, D and Van Leuven, F (1999) Lipoprotein receptor-related protein in brain and in cultured neurons of mice deficient in receptor-associated protein and transgenic for apolipoprotein E4 or amyloid precursor protein. NEUROSCIENCE 94: 315-32

Veinbergs, I, Everson, A, Sagara, Y, Masliah, E (2002) Neurotoxic effects of apolipoprotein E4 are mediated via dysregulation of calcium homeostasis. JOURNAL OF NEUROSCIENCE RESEARCH 67: 379-387

Veinbergs, I, Mallory, M, Sagara, Y and Masliah, E (2000) Vitamin E supplementation prevents spatial learning deficits and dendritic alterations in aged apolipoprotein E-deficient mice. EUROPEAN JOURNAL OF NEUROSCIENCE 12: 4541-4546

Veurink, G, Liu, D, Taddei, K, Perry, G, Smith, MA, Robertson, TA, Hone, E, Groth, DM, Atwood, CS, Martins, RN (2003) Reduction of inclusion body pathology in ApoE-deficient mice fed a combination of antioxidants. FREE RADICAL BIOLOGY AND MEDICINE 34: 1070-1077

Vidal, J, Verchere, CB, Andrikopoulos, S, Wang, F, Hull, RL, Cnop, M, Olin, KL, LeBoeuf, RC, O'Brien, KD, Chait, A, Kahn, SE (2003) The effect of apolipoprotein E deficiency on islet amyloid deposition in human islet amyloid polypeptide transgenic mice. DIABETOLOGIA 46: 71-79

Vincent, B and Smith, JD (2001) Astrocytes down-regulate neuronal beta-amyloid precursor protein expression and modify its processing in an apolipoprotein E isoform-specific manner. EUROPEAN JOURNAL OF NEUROSCIENCE 14: 256-266

Wang, JC, Kwon, JM, Shah, P, Morris, JC and Goate, A (2000) Effect of APOE genotype and promoter polymorphism on risk of Alzheimer's disease. NEUROLOGY 55: 1644-1649

Wang, XY, Luedecking, EK, Minster, RL, Ganguli, M, DeKosky, ST and Kamboh, MI (2001) Lack of association between alpha 2-macroglobulin polymorphisms and Alzheimer's disease. HUMAN GENETICS 108: 105-108

Wavrant-DeVrieze, F, Lambert, JC, Stas, L, Crook, R, Cottel, D, Pasquier, F, Frigard, B, Lambrechts, M, Thiry, E, Amouyel, P, Tur, JP, Chartier-Harlin, MC, Hardy, J and Van Leuven, F (1999) Association between coding variability in the LRP gene and the risk of late-onset Alzheimer's disease. HUMAN GENETICS 104: 432-434

White, F, Nicoll, JAR, Roses, AD and Horsburgh, K (2001) Impaired neuronal plasticity in transgenic mice expressing human apolipoprotein E4 compared to E3 in a model of entorhinal cortex lesion. NEUROBIOLOGY OF DISEASE 8: 611-625

Xu, Q, Brecht, WJ, Weisgraber, KH, Mahley, RW, Huang, YD (2004) Apolipoprotein E4 domain interaction occurs in living neuronal cells as determined by fluorescence resonance energy transfer. JOURNAL OF BIOLOGICAL CHEMISTRY 279: 25511-25516

Yamagata, K, Urakami, K, Ikeda, K, Ji, Y, Adachi, Y, Arai, H, Sasaki, H, Sato, K and Nakashima, K (2001) High expression of apolipoprotein e mRNA in the brains with sporadic Alzheimer's disease. DEMENTIA AND GERIATRIC COGNITIVE DISORDERS 12: 57-62

Yamauchi, K, Tozuka, M, Hidaka, H, Nakabayashi, T, Sugano, M, Katsuyama, T (2002) Isoform-specific effect of apolipoprotein E on endocytosis of beta-amyloid in cultures of neuroblastoma cells. ANNALS OF CLINICAL AND LABORATORY SCIENCE 32: 65-74

Yamauchi, K, Tozuka, M, Hidaka, H, Nakabayashi, T,  Sugano, M, Kondo, Y,  Nakagawara, A and Katsuyama, T (2000) Effect of apolipoprotein AII on the interaction of apolipoprotein E with beta-amyloid: Some Apo(E-AII) complexes inhibit the internalization of beta-amyloid in cultures of neuroblastoma cells. JOURNAL OF NEUROSCIENCE RESEARCH 62: 608-614

Zhang, JG, Yang, JG, Lin, ZX, He, L, Feng, GY, Ma, XY, Wang, CF, Lu, PF, Song, SB, Dong, XZ, St Clair, D and Breen, G (2001) Apolipoprotein E epsilon 4 allele is a risk factor for late-onset Alzheimer's disease and vascular dementia in Han Chinese. INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY 16: 438-439