Alzheimer’s Disease in Man and Transgenic Mice
2001; Elsevier BV; Volume: 158; Issue: 3 Linguagem: Inglês
10.1016/s0002-9440(10)64026-6
ISSN1525-2191
Autores Tópico(s)Cholinesterase and Neurodegenerative Diseases
ResumoThe major risk factors for Alzheimer's disease (AD) are aging, Down's syndrome, genetics, and a positive family history. Most, but not all, studies also find that aging women have a higher risk of developing AD than men.1Moelsa PK Marttila RJ Rinne UK Epidemiology of dementia in a Finnish population.Acta Neurol Scand. 1982; 65: 541-542Crossref PubMed Scopus (170) Google Scholar, 2Jorm AF Korten AE Henderson AS The prevalence of dementia: a quantitative integration of the literature.Acta Psychiatr Scand. 1987; 76: 465-479Crossref PubMed Scopus (1084) Google Scholar, 3Katzman R Aronson M Fuld R Kawas C Brown T Morgenstern H Frishman H Gidez L Eder H Ooi WL Development of dementing illnesses in an 80-year-old volunteer cohort.Ann Neurol. 1989; 25: 317-324Crossref PubMed Scopus (421) Google Scholar, 4Payami H Zareparsi S Montee KR Sexton GI Kaye JA Bird TD Ye CE Wijsman EM Heston LL Litrt M Schellenberg GD Gender difference in apolipoprotein E-associated risk for familial Alzheimer's disease: a possible clue to the higher incidence of Alzheimer's disease in women.Am J Hum Genet. 1996; 58: 803-811PubMed Google Scholar Female apolipoprotein E4 (ApoE4) carriers are also at higher risk than males.5Poirier I Davignon J Bouthillier D Kogan S Bertrand P Gauthier S Apolipoprotein E polymorphism and Alzheimer's disease.Lancet. 1993; 342: 697-699Abstract PubMed Scopus (1171) Google Scholar, 6Corder EH Saunders AM Strittmatter WJ Schmechel DE Gaskell RC Small GW Roses AD Haines JL Pericak-Vance MA Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.Science. 1993; 261: 921-923Crossref PubMed Scopus (7447) Google Scholar, 7Farrer LA Cupples LA van Duijin CM Kurz A Zimmer R Mueller U Green RC Clarke V Shoffner J Wallace DC Chui H Flanagan SD Duara R St George-Hyslop P Auerbach SA Volicer I Wells JM van Broeckhoven C Growdon JH Haines JL Apolipoprotein E genotypes in patients with Alzheimer's disease.Ann Neurol. 1995; 38: 797-808Crossref PubMed Scopus (90) Google Scholar, 8Bretsky PM Buckwalter JG Seeman TE Miller CA Poirier J Schellenberg GD Finch CE Henderson VW Evidence for an interaction between apolipoprotein E genotype, gender, and Alzheimer's disease.Alzheimer Dis Assoc Disord. 1999; 13: 216-221Crossref PubMed Scopus (155) Google Scholar Together with the greater life expectancy of women in developed societies, this means that the majority of patients who live and die with AD are women. The etiology of the higher risk of AD in females is unknown. Perhaps because cognitive functions tend to be more distributed and bilateral in females compared to males, the neuronal disconnections associated with AD may affect women more profoundly. A role for estrogen, by influencing brain development (pre- or postmenarche) or senescence (postmenopause), is a leading hypothesis. In agreement with this notion, some studies suggest a protective effect of estrogen replacement therapy in the risk of developing AD. For example, the risk of developing AD among self-reported estrogen users is about one-third less than among non-users (odds ratio 0.65), and the risk decreases with increased duration and dosage of conjugated equine estrogen, the major form of estrogen replacement in clinical use.9Paganini-Hill A Henderson VW Estrogen deficiency and risk of Alzheimer's disease in women.Am J Epidemiol. 1994; 140: 256-261PubMed Google Scholar, 10Paganini-Hill A Henderson VW Estrogen replacement therapy and risk of Alzheimer's disease.Arch Inter Med. 1996; 156: 2213-2217Crossref PubMed Google Scholar Women who begin menstruation at later, rather than earlier, ages have a higher risk of developing AD.9Paganini-Hill A Henderson VW Estrogen deficiency and risk of Alzheimer's disease in women.Am J Epidemiol. 1994; 140: 256-261PubMed Google Scholar A protective effect of estrogen is also found in a cohort of elderly women in Manhattan. In this study, estrogen use decreases the risk of developing AD by about half (odds ratios 0.40 and 0.50 after adjustment for education) and is independent of ApoE genotype.11Tang MX Jacobs D Stern Y Marder K Schofield P Gurland B Andrews H Mayeux R Effect of oestrogen during menopause on risk and age of onset of Alzheimer's disease.Lancet. 1996; 348: 429-432Abstract Full Text Full Text PDF PubMed Scopus (1596) Google Scholar Other studies, however, find no protective benefit of estrogen replacement therapy12Graves AB White E Koepsell TD Reifler BV van Belle G Larson EB Raskind M A case-control study of Alzheimer's disease.Ann Neurol. 1990; 28: 766-774Crossref PubMed Scopus (201) Google Scholar, 13Brenner DE Kukull WA Stergachis A van Belle G Bowen JD McCormick WC Teri L Larson EB Postmenopausal estrogen replacement therapy and the risk of Alzheimer's disease: a population based case-control study.Am J Epidemiol. 1994; 140: 262-267Crossref PubMed Scopus (284) Google Scholar and suggest that artifactual variables, such as higher socioeconomic status, more education, or better access to medical care among women who are prescribed estrogen, mediate this difference. A subsequent meta-analysis of ten studies, including eight case control and two prospective studies, found a risk reduction of 29% in postmenopausal women taking estrogen replacement therapy compared to untreated women.14Yaffe K Sawaya G Lieberburg I Grady D Estrogen therapy in postmenopausal women.J Am Med Assoc. 1998; 279: 688-695Crossref PubMed Scopus (871) Google Scholar Two more recent case-control studies also demonstrate a risk reduction of 58 to 72%.15Baldereschi M Di Carlo A Lepore V Bracco L Maggi S Grigoletto F Scarlato G Amaducci L Estrogen-replacement therapy and Alzheimer's disease in the Italian Longitudinal Study on Aging.Neurol. 1998; 50: 996-1002Crossref PubMed Scopus (228) Google Scholar, 16Waring SC Rocca WA Petersen RC O'Brien PC Tangalos EG Kokmen E Postmenopausal estrogen replacement therapy and risk of AD: a population-based study.Neurology. 1999; 52: 965-970Crossref PubMed Google Scholar Finally, a recent review of 15 case-control studies published since 1990 suggests that estrogen replacement decreases the risk of developing AD by half.17Melton L Sex is all in the brain: report of a Novartis Foundation symposium in the neuronal and cognitive effects of oestrogens, London UK, 7–9 September 1999.Trends Endocrinol Metabol. 2000; 11: 69-71Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Given this epidemiological evidence, as well as positive results from brief, small, open trials of estrogen replacement in AD,14Yaffe K Sawaya G Lieberburg I Grady D Estrogen therapy in postmenopausal women.J Am Med Assoc. 1998; 279: 688-695Crossref PubMed Scopus (871) Google Scholar three large double-blind placebo-controlled clinical trials of patients with probable AD have now been published—all three with disappointing results.18Henderson VW Paganini-Hill A Miller BL Elble RJ Reyes PF Shoupe D McCleary CA Klein RA Hake AM Farlow MR Estrogen for Alzheimer's disease in women: randomized, double-blind, placebo-controlled trial.Neurology. 2000; 54: 295-301Crossref PubMed Google Scholar, 19Mulnard R Cotman CW Kawas C van Dyck CH Sano M Doody R Koss E Pfeiffer E Jin S Gamst A Grundman M Thomas R Thal LJ Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a 1-year randomized controlled trial.J Am Med Assoc. 2000; 283: 1007-1015Crossref PubMed Scopus (924) Google Scholar, 20Wang PN Liao SQ Liu RS Liu CY Chao HT Lu SR Yu HY Wang SJ Liu HC Effects of estrogen on cognition, mood, and cerebral blood flow in AD. A controlled study.Neurology. 2000; 54: 2061-2066Crossref PubMed Scopus (286) Google Scholar With this information, estrogen replacement therapy cannot currently be recommended as a treatment for AD. Furthermore, the risk of developing AD should not factor into the difficult clinical and personal decision to use estrogen replacement, balancing its beneficial effects on osteoporosis, cardiovascular disease, and other conditions with its carcinogenic potential. The debate now centers on whether the gender effect of AD risk is in fact mediated by postmenopausal estrogen decline and, if so, whether treatment of patients diagnosed with probable AD is too little, too late. Perhaps estrogen must be given in preclinical stages of AD, such as in higher-risk subjects with isolated memory impairment or minimal cognitive impairment, as a preventive therapy. Testing of this hypothesis is underway in 5- and 10-year AD prevention trials, the results of which will be available in 2003 and 2008. Furthermore, the correct estrogen preparation, dosage, and duration, with or without progestins, route of administration (transcutaneous versus oral), and use of drug holidays may all influence the outcome of clinical trials. Transgenic (tg) mouse models have proven to be useful tools in testing hypotheses of AD pathogenesis as well as testing novel therapeutic strategies. Tg human amyloid precursor protein (hAPP) mice recapitulate some, but not all, features of human AD, and may therefore be best described as developing a partial AD-like phenotype with aging. For unclear reasons, the distribution of amyloid pathology in tg hAPP mouse brain is remarkably similar to the human disease. One of the more widely studied hAPP tg mouse lines, Tg2576 mice, developed by Hsiao et al,21Hsiao K Transgenic mice expressing Alzheimer amyloid precursor proteins.Exp Gerontol. 1998; 33: 883-889Crossref PubMed Scopus (107) Google Scholar, 22Hsiao K Chapman P Nilsen S Eckman C Harigaya Y Younkin S Yang F Cole G Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice.Science. 1996; 274: 99-102Crossref PubMed Scopus (3733) Google Scholar expresses the familial AD gene hAPP swe (Swedish mutation; APPK670N/M671L in the APP770 numbering system) in a C57B6/SJL genetic background. The neuron-specific prion protein promoter drives expression of the transgene. With aging, Tg2576 mice exhibit a phenotype that includes learning and memory deficits, an abnormal pattern of glucose metabolism in brain, and pathological changes including amyloid plaque deposition, elevated Aβ40 and Aβ42 levels, neuritic changes, phosphorylated tau epitopes, α-synuclein-positive dystrophic neurites, gliosis, and inflammatory responses; however, aging mice develop neither neurofibrillary tangles nor significant neuronal loss.21Hsiao K Transgenic mice expressing Alzheimer amyloid precursor proteins.Exp Gerontol. 1998; 33: 883-889Crossref PubMed Scopus (107) Google Scholar, 22Hsiao K Chapman P Nilsen S Eckman C Harigaya Y Younkin S Yang F Cole G Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice.Science. 1996; 274: 99-102Crossref PubMed Scopus (3733) Google Scholar, 23Irizarry MC McNamara M Fedorchak K Hsiao K Hyman BT AppSw transgenic mice develop age-related Abeta deposits and neuropil abnormalities, but no neuronal loss in CA1.J Neuropathol Exp Neurol. 1997; 56: 965-973Crossref PubMed Scopus (578) Google Scholar, 24Frautschy SA Yang F Irizarry M Hyman B Saido TC Hsiao K Cole GM Microglial response to amyloid plaques in APPsw transgenic mice.Am J Pathol. 1998; 152: 307-317PubMed Google Scholar, 25Holcomb L Gordon MN McGowan E Yu X Benkovic S Jantzen P Wright K Saad I Mueller R Morgan D Sanders S Zehr C O'Campo K Hardy J Prada CM Eckman C Younkin S Hsiao K Duff K Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes.Nat Med. 1998; 4: 97-100Crossref PubMed Scopus (1179) Google Scholar, 26Pappolla MA Chyan YJ Omar RA Hsiao K Perry G Smith GA Bozner P Evidence of oxidative stress and in vivo neurotoxicity of beta-amyloid in a transgenic mouse model of Alzheimer's disease: a chronic oxidative paradigm for testing antioxidant therapies in vivo.Am J Pathol. 1998; 152: 871-877PubMed Google Scholar, 27Smith MA Hirai K Hsiao K Pappolla MA Harris PL Siedlack SL Tabaton M Perry G Amyloid-β deposition in Alzheimer transgenic mice is associated with oxidative stress.J Neurochem. 1998; 70: 2212-2215Crossref PubMed Scopus (525) Google Scholar, 28Benzing WC Wujek JR Ware EK Shaffer D Ashe KH Younkin SG Brunden KR Evidence for glial-mediated inflammation in aged APP(SW) transgenic mice.Neurobiol Aging. 1999; 20: 581-589Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar, 29Chapman PF White GL Jones MW Cooper-Blacketer D Marshall VJ Irizarry M Younkin L Good MA Bliss TV Hyman BT Younkin SG Hsiao KK Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice.Nat Neurosci. 1999; 2: 271-276Crossref PubMed Scopus (825) Google Scholar, 30King DL Arendash GW Crawford F Sterk T Menendez J Mullan MJ Progressive and gender-dependent cognitive impairment in the APPsw transgenic mouse model for Alzheimer's disease.Behavioural Brain Res. 1999; 103: 145-162Crossref PubMed Scopus (199) Google Scholar, 31Mehlhorn G Hollborn M Schliebs R Induction of cytokines in glial cells surrounding cortical beta-amyloid plaques in transgenic Tg2576 mice with Alzheimer pathology.Int J Dev Neurosci. 2000; 18: 423-431Crossref PubMed Scopus (186) Google Scholar, 32Takeuchi A Irizarry MC Duff K Saido TC Hsiao Ashe K Hasegawa M Mann DM Hyman BT Iwatsubo T Age-related amyloid beta deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amyloid beta precursor protein Swedish mutant is not associated with global neuronal loss.Am J Pathol. 2000; 157: 331-339Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar, 33Yang F Ueda K Chen P Ashe KH Cole CM Plaque-associated alpha-synuclein (NACP) pathology in aged transgenic mice expressing amyloid precursor protein.Brain Res. 2000; 853: 381-383Crossref PubMed Scopus (55) Google Scholar Cholinergic abnormalities in the immediate vicinity of amyloid plaques are apparent in immunostained brain sections from older hAPP tg34Sturchler-Pierrat C Abramowski D Duke M Wiederhold KH Mistl C Rothacher S Ledermann B Burki K Frey P Paganetti PA Waridel C Calhoun ME Jucker M Probst A Staufenbiel M Sommer B Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology.Proc Natl Acad Sci USA. 1997; 94: 13287-13292Crossref PubMed Scopus (1265) Google Scholar and hPresenilin-1 (mutant)/hAPP double tg mice,35Wong TP Debeir T Duff K Cuello AC Reorganization of cholinergic terminals in the cerebral cortex and hippocampus in transgenic mice carrying mutated presenilin-1 and amyloid precursor protein protein transgenes.J Neurosci. 1999; 19: 2706-2716PubMed Google Scholar but more macroscopic studies of cholinergic function have not been reported. Amyloid plaque deposition in aging hAPP tg mice may be modulated pharmacologically, immunologically, and genetically. For example, amyloid pathology is accelerated in hPresenilin-1 (mutant)/hAPP double tg mice,25Holcomb L Gordon MN McGowan E Yu X Benkovic S Jantzen P Wright K Saad I Mueller R Morgan D Sanders S Zehr C O'Campo K Hardy J Prada CM Eckman C Younkin S Hsiao K Duff K Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes.Nat Med. 1998; 4: 97-100Crossref PubMed Scopus (1179) Google Scholar and absent in murine ApoE null (−/−)/hAPP tg mice.36Bales KR Verina T Dodel RC Du Y Altstiel L Bender M Hyslop P Johnstone EM Little SP Cummings DJ Piccardo P Ghetti B Paul SM Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition.Nat Genet. 1997; 17: 263-264Crossref PubMed Scopus (713) Google Scholar In the latter mice, hApoE4 transgene expression promotes more fibrillar amyloid deposition than hApoE3.37Holtzman DM Bales KR Tenkova T Fagan AM Parsadanian M Sartorius LJ Mackey B Olney J McKeel D Wozniak D Paul SM Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease.Proc Natl Acad Sci USA. 2000; 97: 2892-2897Crossref PubMed Scopus (737) Google Scholar Human transforming growth factor β1/hAPP double tg mice develop increased Aβ deposition within plaques, with a greater proportion of meningeal and vascular deposition, reflecting a role of inflammation in amyloidogenesis.38Wyss-Coray T Masliah E Mallory M McConlogue L Johnson-Wood K Lin C Mucke L Amyloidogenic role of cytokine TGF-beta1 in transgenic mice and in Alzheimer's disease.Nature. 1997; 389: 603-606Crossref PubMed Scopus (364) Google Scholar Amyloid plaque deposition and behavioral decline in hAPP tg mice is prevented, and perhaps partially reversed, by immunization with intraperitoneal Aβ4239Schenk D Barbour R Dunn W Gordon G Grajeda H Guido T Hu K Huang J Johnson-Wood K Khan K Kholodenko D Lee M Liao Z Lieberburg I Motter R Mutter L Soriano F Shopp G Vasquez N Vandevert C Shannan W Wogulis M Yednock T Games D Seubert P Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse.Nature. 1999; 400: 173-177Crossref PubMed Scopus (2979) Google Scholar, 40Janus C Pearson J McLaurin J McLaurin J Mathews PM Jiang Y Schmidt SD Chishti MA Horne P Heslin D French J Mount HTJ Nixon RA Mercken M Bergeron C Fraser PE St George-Hyslop P Westaway D Aβ peptide immunization reduces behavioral impairment and plaques in a mouse model of Alzheimer's disease.Nature. 2000; 408: 979-982Crossref PubMed Scopus (1382) Google Scholar, 41Morgan D Diamond DM Gottschall PE Ugen KE Dickey C Hardy J Duff K Jantzen P DiCarlo G Wilcock D Connor K Hatcher J Hope C Gordon M Arendash GW Aβ vaccination prevents memory loss in an animal model of Alzheimer's disease.Nature. 2000; 408: 982-985Crossref PubMed Scopus (1434) Google Scholar; mucosal (nasal) administration of Aβ40 may be somewhat less effective.42Weiner HL Lemere CA Maron R Spooner ET Grenfell TJ Mori C Issazadeh S Hancock WW Selkoe DJ Nasal administration of amyloid-β peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease.Ann Neurol. 2000; 48: 567-579Crossref PubMed Scopus (307) Google Scholar Protection from amyloid deposition may be transferred passively by immunoglobulin, suggesting activation of an immunoglobulin and phagocytic microglial clearance mechanism.43Bard F Cannon C Barbour R Burke R-L Games D Grajeda H Guido T Hu K Huang J Johnson-Wood K Khan K Kholodenko D Lee M Lieberburg I Motter R Nguyen M Soriano F Vasquez N Weiss N Welch B Seubert P Schenk D Yednock T Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer's disease.Nat Med. 2000; 6: 916-919Crossref PubMed Scopus (1835) Google Scholar The response to immunization (as measured by serum titer to Aβ) may correlate with lower amyloid burden in brain. Immunization does not prevent all amyloid deposition, perhaps due to poor penetration of immunoglobulins across the blood-brain barrier. Taken to an extreme, one may speculate that the risk of developing sporadic AD with aging may correlate with innate immune, inflammatory, or cellular responses to amyloid deposition in brain. Finally, amyloid pathology in hAPP tg mice may be prevented by pharmacological treatment with the phosphatidylinositol kinase inhibitor wortmannin, which inhibits Aβ production in vitro,44Haugabook SJ Le T Yager D Zenk B Healy BM Echman EA Prada C Younkin L Murphy P Pinnix I Onstead L Sambamurti K Golde TE Dickson D Younkin SG Eckman CB Reduction of Aβ accumulation in the Tg2576 animal model of Alzheimer's disease after oral administration of the phosphatidylinositol kinase inhibitor wortmannin.FASEB J. 2001; 15: 16-18PubMed Google Scholar the Cu2+/Zn2+-chelator/antibiotic clioquinol, which blocks amyloid fibril formation in vitro,45Helmuth L An antibiotic to treat Alzheimer's? (editorial).Science. 2000; 290: 1273-1274Crossref PubMed Google Scholar or the nonsteroidal anti-inflammatory drug ibuprofen.46Lim GP Yang F Chu T Chen P Beech W Teter B Tran T Ubeda O Hsiao Ashe K Frautschy SA Cole GM Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease.J Neurosci. 2000; 20: 5709-5714Crossref PubMed Google Scholar The efficacy of this wide variety of pharmacological treatments in preventing amyloid deposition in tg AD mice reveals multiple alternative and competing therapeutic strategies, and suggests that we may ultimately employ a clinical cocktail for AD prevention in humans. Novel therapeutics targeting the recently identified γ-secretase complex and β-secretases that generate Aβ40 and Aβ42 from APP are also being vigorously pursued.47Selkoe DJ Translating cell biology into therapeutic advances in Alzheimer's disease.Nature. 1999; 399: A23-A31Crossref PubMed Scopus (1537) Google Scholar Taken together, these studies reveal mechanisms of amyloidogenesis and new therapeutic targets based on the amyloid hypothesis of AD. None of these studies examined gender as a variable. Furthermore, the obvious studies of estrogen treatment trials in tg hAPP mice have not yet been reported. Ovariectomy increases Aβ levels in guinea pig brain (1.5-fold for Aβ40 and 1.8-fold for Aβ42), and this effect is partly reversed with either low-dose or high-dose 17β-estradiol treatment.48Petanceska SS Nagy V Frail D Gandy S Ovariectomy and 17β-estradiol modulate the levels of Alzheimer's amyloid β peptides in brain.Neurology. 2000; 54: 2212-2217Crossref PubMed Scopus (158) Google Scholar This study leads directly to a hypothesized acceleration of pathology in ovariectomized hAPP tg mice and a beneficial effect of estrogen replacement in the prevention of amyloidogenesis in aging hAPP tg mouse brain. In support of these hypotheses, Callahan et al49Callahan MJ Lipinski WJ Bian F Durham RA Pack A Walker LC Augmented senile plaque load in aged female β-amyloid precursor protein transgenic mice.Am J Pathol. 2001; 158: 1173-1177Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar report in this issue of The American Journal of Pathology that in aging Tg2576 mice, females exhibit a much greater amyloid plaque burden in brain than males. Given the current clinical quandary regarding the results of estrogen replacement in women with AD, this study could not have been more timely. Amyloid load was measured by a quantitative areal analysis of stained brain sections. In 91 mice studied at 15 months of age, the area occupied by plaques in female Tg2576 mice was nearly three times that in males. A slight trend was apparent but insignificant in female mice at ages 8 and 12 months. Amyloid plaque deposition begins in earnest between 12 and 15 months of age, and thus coincides with the age of mouse anestrus. This is the first report of a gender effect on amyloid deposition in hAPP tg mice, and reveals that tg hAPP mice recapitulate yet another feature of the human disease: the gender effect. There are no data regarding a gender difference in amyloid load in other hAPP tg mouse lines. Neither is there information regarding a gender effect in hTau tg mice that develop neurofibrillary tangles. Again the question of mechanism arises, and postmenopausal estrogen loss is hypothesized as a leading candidate. Several mechanisms may be proposed; they are not mutually exclusive. The first category of possible mechanisms is more direct and based on known pleiotropic effects of estrogen on neurons and brain: 1) Estrogen down-regulates Aβ generation from APP metabolism in cultured cells.50Chang D Kwan J Timiras PS Estrogens influence growth, maturation and amyloid beta-peptide production in neuroblastoma cells and in a beta-APP transfected kidney 293 cell line.Adv Exp Med Biol. 1997; 429: 261-271Crossref PubMed Scopus (54) Google Scholar, 51Xu H Gouras GK Greenfield JP Vincent B Naslund J Mazzarelli L Fried G Jovanovic JN Seeger M Relkin NR Liao F Checler F Buxbaum JD Chait BT Thinakaran G Sisodia SS Wang R Greengard P Gandy S Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides.Nat Med. 1998; 4: 447-451Crossref PubMed Scopus (519) Google Scholar Thus, the decline of estrogen with menopause may result in increased Aβ generation. Data to test this hypothesis with tg hAPP mice are lacking, however. As mentioned, there are no published studies of estrogen deprivation or treatment in tg hAPP mice. 2) Estrogen has trophic effects on neurons, including cholinergic neurons, and may protect them from morbidity and mortality.52Luine V Estradiol increased choline acetyltransferase activity in specific basal forebrain nuclei and projection areas in female rats.Exp Neurol. 1985; 89: 484-490Crossref PubMed Scopus (495) Google Scholar, 53McEwen BS Woolley C Estradiol and progesterone regulate neuronal structure and synaptic connectivity in adult as well as developing brain.Exp Gerontol. 1994; 29: 431-436Crossref PubMed Scopus (274) Google Scholar, 54Lustig RH Sex hormone modulation of neural development in vitro.Horm Behav. 1994; 28: 383-395Crossref PubMed Scopus (77) Google Scholar, 55Keefe D Garcia-Segura M Naftolin F New insights into estrogen action on the brain.Neurobiol Aging. 1994; 15: 495-497Abstract Full Text PDF PubMed Scopus (24) Google Scholar However, since Tg2576 mice do not demonstrate significant neuronal loss, this mechanism may be more applicable to the human disease than to hAPP tg mice. 3) Estrogen is an antioxidant, and thus may decrease neuronal damage caused by oxidative stress.56Behl C Widmann M Trapp T Holsboer F 17β Estradiol protects neurons from oxidative stress-induced cell death in vitro.Biochem Biophys Res Comm. 1995; 216: 473-482Crossref PubMed Scopus (597) Google Scholar, 57Gridley KE Green PS Simpkins JW Low concentrations of estradiol reduce beta-amyloid (25–35)-induced toxicity, lipid peroxidation and glucose utilization in human SK-N-SH neuroblastoma cells.Brain Res. 1997; 778: 158-165Crossref PubMed Scopus (128) Google Scholar Two other antioxidants, α-tocopherol (vitamin E) and selegiline, have clinical benefits in patients with probable AD.58Sano M Ernesto C Thomas RG Klauber MR Schafer K Grundman M Woodbury P Growdon J Cotman CW Pfeiffer E Schneider LS Thal LJ A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease.New Engl J Med. 1997; 336: 1216-1222Crossref PubMed Scopus (2335) Google Scholar In this study, clinical benefits were defined primarily by functional outcome measures; however, no benefit of treatment on cognitive (secondary) outcomes was found. The second category of possible mechanisms contains those which may indirectly affect another risk factor of AD: 4) ApoE appears to play a role in Aβ deposition and/or clearance from brain. Since estrogen up-regulates ApoE expression,59Srivastava RA Srivastava N Averna M Lin RC Korach KS Lubahn DB Schonfeld G Estrogen upregulates apolipoprotein E (ApoE) gene expression by increasing ApoE mRNA in the translating pool via the estrogen receptor alpha-mediated pathway.J Biol Chem. 1997; 27: 33360-33366Crossref Scopus (138) Google Scholar, 60Stone DJ Rozovsky I Morgan TE Anderson CP Hajian H Finch CE Astrocytes and microglia respond to estrogen with increased apoE mRNA in vivo and in vitro.Exp Neurol. 1997; 143: 313-318Crossref PubMed Scopus (222) Google Scholar the gender effect may be mediated by a postmenopausal decline in circulating ApoE levels.61Kushwaha RS Foster DM Barrett RHR Carey KD Bernard MG Metabolic regulation of plasma apolipoprotein E by estrogen and progesterone in the baboon (Papio sp.).Metabolism. 1991; 40: 93-100Abstract Full Text PDF PubMed Scopus (36) Google Scholar, 62Muesing RA Miller VT LaRosa JC Stoy DB Phillips EA Effects of unopposed conjugated equine estrogen on lipoprotein composition and apolipoprotein-E distribution.J Clin Endocrinol Met. 1992; 75: 1250-1254PubMed Google Scholar 5) Estrogen regulates cholesterol levels, and elevated cholesterol promotes Aβ generation in cell culture and animal models.63Refolo LM Pappolla MA Malester B LaFrancois J Bryant-Thomas T Wang R Tint GS Sambamurti K Duff K Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model.Neurobiol Dis. 2000; 7: 321-331Crossref PubMed Scopus (895) Google Scholar This effect of estrogen on cholesterol levels may be independent of ApoE-mediated clearance mechanisms. 6) Although not a known risk factor for AD, the immune, inflammatory, and glial response to amyloid in tg hAPP mouse brain modulates AD pathology. Likewise, estrogen levels may influence the immune and inflammatory response to amyloid deposition in brain.64Bauer J Ganet U Strauss S Stadtrnueller G Frommberger U Bauer H Volk B Berger M The participation of interleukin-6 in the pathogenesis of Alzheimer's disease.Res Immunol. 1992; 143: 650-653Crossref PubMed Scopus (105) Google Scholar Clearly, multiple mechanisms of estrogen may alter (i) Aβ generation from APP, (ii) the deposition and clearance of Aβ in brain, or (iii) cellular responses to amyloid. Although these effects suggest roles for estrogen, they may not explain the gender difference seen in aging Tg2576 mice, nor the increased risk of AD in women. Callahan et al49Callahan MJ Lipinski WJ Bian F Durham RA Pack A Walker LC Augmented senile plaque load in aged female β-amyloid precursor protein transgenic mice.Am J Pathol. 2001; 158: 1173-1177Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar also measure Aβ40 and Aβ42 levels from soluble and insoluble fractions of tg mouse brain tissue by enzyme-linked immunosorbent assay. In contrast to the marked gender effect on plaque burden in brain, the difference in soluble Aβ40 levels is subtle. Soluble Aβ40 levels are statistically significantly higher in 15-month-old female mice compared to males, but not markedly higher. As may be expected by the greater amyloid burden found in female mice, insoluble Aβ40 levels reveal a greater gender difference than soluble Aβ40. This difference, however, is far less than expected, leading to discussion of a missing pool of Aβ. There were no significant gender differences in the much lower levels of either soluble or insoluble Aβ42. In contrast to Hsiao et al,22Hsiao K Chapman P Nilsen S Eckman C Harigaya Y Younkin S Yang F Cole G Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice.Science. 1996; 274: 99-102Crossref PubMed Scopus (3733) Google Scholar the authors find no correlation between plaque load and performance on a behavioral task (Morris water maze), male or female, and suggest that this may be an insufficiently sensitive task to detect a gender difference. King et al30King DL Arendash GW Crawford F Sterk T Menendez J Mullan MJ Progressive and gender-dependent cognitive impairment in the APPsw transgenic mouse model for Alzheimer's disease.Behavioural Brain Res. 1999; 103: 145-162Crossref PubMed Scopus (199) Google Scholar report gender differences in several behavioral tasks in Tg2576 mice at 3 and 9 months of age, that is, before significant Aβ and amyloid deposits develop in the brain. No other reports on the effect of gender on behavior of Tg2576 mice have been published. These data bring up the debate as to which forms of Aβ are deleterious: intraneuronal versus extracellular, soluble versus insoluble, monomers, oligomers, or amyloid fibrils? Because behavioral and electrophysiological abnormalities precede amyloid deposition in brains of Tg2576 and other hAPP tg mice, soluble and oligomeric, and perhaps intraneuronal, Aβ is implicated in various neurotoxic mechanisms.22Hsiao K Chapman P Nilsen S Eckman C Harigaya Y Younkin S Yang F Cole G Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice.Science. 1996; 274: 99-102Crossref PubMed Scopus (3733) Google Scholar, 29Chapman PF White GL Jones MW Cooper-Blacketer D Marshall VJ Irizarry M Younkin L Good MA Bliss TV Hyman BT Younkin SG Hsiao KK Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice.Nat Neurosci. 1999; 2: 271-276Crossref PubMed Scopus (825) Google Scholar, 65Hsia AY Masliah E McConlogue L Yu G-Q Tatsuno G Hu K Kholodenko D Malenka RC Nicoll RA Mucke L Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models.Proc Natl Acad Sci USA. 1999; 96: 3228-3233Crossref PubMed Scopus (1001) Google Scholar, 66Mucke L Masliah E Yu G-Q Mallory M Rockenstein EM Tatsuno G Hu K Kholodenko K McConlogue L High-level neuronal expression of Aβ1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation.J Neurosci. 2000; 20: 4050-4058Crossref PubMed Google Scholar Given the more marked gender difference in plaque burden as opposed to soluble Aβ levels and no effect on behavioral decline (Morris water maze) of Tg2576 mice with aging,49Callahan MJ Lipinski WJ Bian F Durham RA Pack A Walker LC Augmented senile plaque load in aged female β-amyloid precursor protein transgenic mice.Am J Pathol. 2001; 158: 1173-1177Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar then perhaps the more important pathogenic variable with respect to behavior is soluble Aβ levels. Amyloid plaques in brain may develop as a threshold or saturation phenomenon and sequester Aβ peptides in a more inert form that produces only local toxicity. This notion has been suggested in other neurodegenerative diseases with abnormal (intracellular) protein aggregates. This study raises more questions than it answers and generates new testable hypotheses. Tg2576 mice recapitulate another feature of human AD—the gender effect—despite the behavioral and pathological shortcomings of this tg mouse as a model of human disease.49Callahan MJ Lipinski WJ Bian F Durham RA Pack A Walker LC Augmented senile plaque load in aged female β-amyloid precursor protein transgenic mice.Am J Pathol. 2001; 158: 1173-1177Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar Although independent confirmation in Tg2576 (or other hAPP tg) mice is lacking, these animal models may be useful in dissecting the mechanism(s) of the gender effect on amyloidogenesis in Tg2576 mice, and perhaps in man. This mechanism may or may not involve the pleiotropic effects of estrogens in the brain. A novel therapy for AD may result from identifying the risk factor(s) in female tg hAPP mice, or conversely, in defining the protective factor(s) in males. Interestingly, testosterone also reduces secretion of Aβ peptides from cultured cells.67Gouras BK Xu H Gross RS Greenfield JP Hai B Wang R Greengard P Testosterone reduces neuronal secretion of Alzheimer's beta-amyloid peptides.Proc Natl Acad Sci USA. 2000; 97: 1202-1205Crossref PubMed Scopus (274) Google Scholar A more gradual decline in testosterone levels with andropause (progressive androgen deficiency of the aging male) may increase the risk of developing AD in aging men, but replacement therapy again engenders an increased risk of cancer. Whatever the mechanism, these data provide an important clue as to the variables influencing age-dependent amyloid plaque deposition in Tg2576 mouse brain. These data also warn that all future investigations of Tg2576 mice, and perhaps other hAPP tg mice, must include gender as a variable in pathological mechanisms as well as treatment outcomes, particularly in studies measuring amyloid burden in brain. Prevention of age-dependent amyloid deposition and behavioral/cognitive decline in tg hAPP mice and in man will be the ultimate test of the amyloid hypothesis.47Selkoe DJ Translating cell biology into therapeutic advances in Alzheimer's disease.Nature. 1999; 399: A23-A31Crossref PubMed Scopus (1537) Google Scholar The current race between various pharmacological versus immunological, and, perhaps ultimately, genetic strategies for AD will benefit millions of future patients, the majority of whom will be women.
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