Neuropathology and treatment of Alzheimer disease: did we lose the forest for the trees?

References

• Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch. Neurol.60(8), 1119–1122 (2003).
   PubMed Web of Science ®Google Scholar
• Ernst RL, Hay JW. The US economic and social costs of Alzheimer’s disease revisited. Am. J. Public Health84(8), 1261–1264 (1994).
   PubMed Web of Science ®Google Scholar
• Lee HG, Zhu X, Nunomura A, Perry G, Smith MA. Amyloid-β vaccination: testing the amyloid hypothesis?: heads we win, tails you lose! Am. J. Pathol.169(3), 738–739 (2006).
   PubMedGoogle Scholar
• Perry G, Nunomura A, Raina AK, Smith MA. Amyloid-β junkies. Lancet355(9205), 757 (2000).
   PubMed Web of Science ®Google Scholar
• Smith MA, Atwood CS, Joseph JA, Perry G. Predicting the failure of amyloid-β vaccine. Lancet359(9320), 1864–1865 (2002).
   PubMed Web of Science ®Google Scholar
• Castellani RJ, Lee HG, Zhu X et al. Neuropathology of Alzheimer disease: pathognomonic but not pathogenic. Acta Neuropathol. (Berl.)111(6), 503–509 (2006).
   PubMed Web of Science ®Google Scholar
• Lee HG, Zhu X, Petersen RB, Perry G, Smith MA. Amyloids, aggregates and neuronal inclusions: good or bad news for neurons? Currr. Med. Chem. – Immun. Endoc. Metab. Agents3, 293–298 (2003).
   Google Scholar
• Joseph J, Shukitt-Hale B, Denisova NA et al. Copernicus revisited: amyloid β in Alzheimer’s disease. Neurobiol. Aging22(1), 131–146 (2001).
   PubMed Web of Science ®Google Scholar
• Perry G, Avila J, Kinoshita J, Smith MA. Alzheimer’s Disease: A Century of Scientific and Clinical Research. IOS Press, Amsterdam, The Netherlands (2006).
   Google Scholar
• Selkoe DJ, Abraham CR, Podlisny MB, Duffy LK. Isolation of low-molecular-weight proteins from amyloid plaque fibers in Alzheimer’s disease. J. Neurochem.46(6), 1820–1834 (1986).
   PubMed Web of Science ®Google Scholar
• Masters CL, Simms G, Weinman NA et al. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl Acad. Sci. USA82(12), 4245–4249 (1985).
   PubMed Web of Science ®Google Scholar
• Grundke-Iqbal I, Iqbal K, Quinlan M et al. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J. Biol. Chem.261(13), 6084–6089 (1986).
   PubMed Web of Science ®Google Scholar
• Wood JG, Mirra SS, Pollock NJ, Binder LI. Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau (tau). Proc. Natl Acad. Sci. USA83(11), 4040–4043 (1986).
   PubMed Web of Science ®Google Scholar
• Mirra SS, Heyman A, McKeel D et al. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology41(4), 479–486 (1991).
   PubMed Web of Science ®Google Scholar
• Khachaturian ZS. Diagnosis of Alzheimer’s disease. Arch. Neurol.42(11), 1097–1105 (1985).
   PubMed Web of Science ®Google Scholar
• Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Neurobiol. Aging18(4 Suppl.), S1–S2 (1997).
   PubMed Web of Science ®Google Scholar
• Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. (Berl.)82(4), 239–259 (1991).
   PubMed Web of Science ®Google Scholar
• Perry G, Raina AK, Cohen ML, Smith MA. When hypotheses dominate. The Scientist18, 6 (2004).
   Google Scholar
• Bennett DA, Schneider JA, Arvanitakis Z et al. Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology66(12), 1837–1844 (2006).
   PubMed Web of Science ®Google Scholar
• Tiraboschi P, Sabbagh MN, Hansen LA et al. Alzheimer disease without neocortical neurofibrillary tangles: “a second look”. Neurology62(7), 1141–1147 (2004).
   PubMedGoogle Scholar
• Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science297(5580), 353–356 (2002).
   PubMed Web of Science ®Google Scholar
• Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science256(5054), 184–185 (1992).
   PubMed Web of Science ®Google Scholar
• Lee HG, Zhu X, Nunomura A, Perry G, Smith MA. Amyloid β: the alternate hypothesis. Curr. Alzheimer Res.3(1), 75–80 (2006).
   PubMedGoogle Scholar
• Kumar-Singh S, Theuns J, Van Broeck B et al. Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Aβ42 and decreased Aβ40. Hum. Mutat.27(7), 686–695 (2006).
   PubMed Web of Science ®Google Scholar
• Bentahir M, Nyabi O, Verhamme J et al. Presenilin clinical mutations can affect γ-secretase activity by different mechanisms. J. Neurochem.96(3), 732–742 (2006).
   PubMed Web of Science ®Google Scholar
• Kimberly WT, Zheng JB, Guenette SY, Selkoe DJ. The intracellular domain of the β-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner. J. Biol. Chem.276(43), 40288–40292 (2001).
   PubMed Web of Science ®Google Scholar
• Sisodia SS, Koo EH, Beyreuther K, Unterbeck A, Price DL. Evidence that β-amyloid protein in Alzheimer’s disease is not derived by normal processing. Science248(4954), 492–495 (1990).
   PubMed Web of Science ®Google Scholar
• Shoji M, Golde TE, Ghiso J et al. Production of the Alzheimer amyloid β protein by normal proteolytic processing. Science258(5079), 126–129 (1992).
   PubMed Web of Science ®Google Scholar
• Haass C, Schlossmacher MG, Hung AY et al. Amyloid β-peptide is produced by cultured cells during normal metabolism. Nature359(6393), 322–325 (1992).
   PubMed Web of Science ®Google Scholar
• Sinha S, Lieberburg I. Cellular mechanisms of β-amyloid production and secretion. Proc. Natl Acad. Sci. USA96(20), 11049–11053 (1999).
   PubMed Web of Science ®Google Scholar
• Gruninger-Leitch F, Schlatter D, Kung E, Nelbock P, Dobeli H. Substrate and inhibitor profile of BACE (β-secretase) and comparison with other mammalian aspartic proteases. J. Biol. Chem.277(7), 4687–4693 (2002).
   PubMed Web of Science ®Google Scholar
• Scheuner D, Eckman C, Jensen M et al. Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat. Med.2(8), 864–870 (1996).
   PubMed Web of Science ®Google Scholar
• De Strooper B, Saftig P, Craessaerts K et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature391(6665), 387–390 (1998).
   PubMed Web of Science ®Google Scholar
• Wolfe MS, Xia W, Moore CL et al. Peptidomimetic probes and molecular modeling suggest that Alzheimer’s γ-secretase is an intramembrane-cleaving aspartyl protease. Biochemistry (Mosc.)38(15), 4720–4727 (1999).
   Google Scholar
• Goutte C, Tsunozaki M, Hale VA, Priess JR. APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos. Proc. Natl Acad. Sci. USA99(2), 775–779 (2002).
   PubMed Web of Science ®Google Scholar
• Francis R, McGrath G, Zhang J et al. aph-1 and pen-2 are required for Notch pathway signaling, γ-secretase cleavage of βAPP, and presenilin protein accumulation. Dev. Cell.3(1), 85–97 (2002).
   PubMed Web of Science ®Google Scholar
• Becher B, Prat A, Antel JP. Brain-immune connection: immuno-regulatory properties of CNS-resident cells. Glia29(4), 293–304 (2000).
   PubMed Web of Science ®Google Scholar
• Monsonego A, Zota V, Karni A et al. Increased T cell reactivity to amyloid β protein in older humans and patients with Alzheimer disease. J. Clin. Invest.112(3), 415–422 (2003).
   PubMed Web of Science ®Google Scholar
• Schenk D, Barbour R, Dunn W et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature400(6740), 173–177 (1999).
   PubMed Web of Science ®Google Scholar
• Morgan D, Diamond DM, Gottschall PE et al. A β peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature408(6815), 982–985 (2000).
   PubMed Web of Science ®Google Scholar
• Janus C, Pearson J, McLaurin J et al. A β peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature408(6815), 979–982 (2000).
   PubMed Web of Science ®Google Scholar
• Bard F, Cannon C, Barbour R et al. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med.6(8), 916–919 (2000).
   PubMed Web of Science ®Google Scholar
• Nicoll JA, Wilkinson D, Holmes C et al. Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report. Nat. Med.9(4), 448–452 (2003).
   PubMed Web of Science ®Google Scholar
• Mucke L, Masliah E, Yu GQ et al. High-level neuronal expression of aβ 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J. Neurosci.20(11), 4050–4058 (2000).
   PubMed Web of Science ®Google Scholar
• Dodart JC, Bales KR, Gannon KS et al. Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer’s disease model. Nat. Neurosci.5(5), 452–457 (2002).
   Google Scholar
• Selkoe DJ. Alzheimer’s disease is a synaptic failure. Science298(5594), 789–791 (2002).
   PubMed Web of Science ®Google Scholar
• Patton RL, Kalback WM, Esh CL et al. Amyloid-β peptide remnants in AN-1792-immunized Alzheimer’s disease patients: a biochemical analysis. Am. J. Pathol.169(3), 1048–1063 (2006).
   PubMed Web of Science ®Google Scholar
• Klein WL, Krafft GA, Finch CE. Targeting small Aβ oligomers: the solution to an Alzheimer’s disease conundrum? Trends Neurosci.24(4), 219–224 (2001).
   PubMed Web of Science ®Google Scholar
• Chromy BA, Nowak RJ, Lambert MP et al. Self-assembly of Aβ(1-42) into globular neurotoxins. Biochemistry (Mosc.)42(44), 12749–12760 (2003).
   Google Scholar
• Bitan G, Lomakin A, Teplow DB. Amyloid β-protein oligomerization: prenucleation interactions revealed by photo-induced cross-linking of unmodified proteins. J. Biol. Chem.276(37), 35176–35184 (2001).
   PubMed Web of Science ®Google Scholar
• Younkin SG. The role of A β 42 in Alzheimer’s disease. J. Physiol. Paris92(3–4), 289–292 (1998).
   PubMedGoogle Scholar
• Rottkamp CA, Atwood CS, Joseph JA et al. The state versus amyloid-β: the trial of the most wanted criminal in Alzheimer disease. Peptides23(7), 1333–1341 (2002).
   PubMed Web of Science ®Google Scholar
• Smith MA, Joseph JA, Perry G. Arson. Tracking the culprit in Alzheimer’s disease. Ann. NY Acad. Sci.924, 35–38 (2000).
   PubMed Web of Science ®Google Scholar
• Smith MA, Casadesus G, Joseph JA, Perry G. Amyloid-β and tau serve antioxidant functions in the aging and Alzheimer brain. Free Radic. Biol. Med.33(9), 1194–1199 (2002).
   PubMed Web of Science ®Google Scholar
• Perry G, Castellani RJ, Hirai K, Smith MA. Reactive oxygen species mediate cellular damage in Alzheimer disease. J. Alzheimers Dis.1(1), 45–55 (1998).
   PubMedGoogle Scholar
• Reiman EM, Caselli RJ, Yun LS et al. Preclinical evidence of Alzheimer’s disease in persons homozygous for the ε 4 allele for apolipoprotein E. N. Engl. J. Med.334(12), 752–758 (1996).
   PubMed Web of Science ®Google Scholar
• Hirai K, Aliev G, Nunomura A et al. Mitochondrial abnormalities in Alzheimer’s disease. J. Neurosci.21(9), 3017–3023 (2001).
   PubMed Web of Science ®Google Scholar
• Smith CD, Carney JM, Tatsumo T et al. Protein oxidation in aging brain. Ann. NY Acad. Sci.663, 110–119 (1992).
   PubMed Web of Science ®Google Scholar
• Smith MA, Rottkamp CA, Nunomura A, Raina AK, Perry G. Oxidative stress in Alzheimer’s disease. Biochim. Biophys. Acta1502(1), 139–144 (2000).
   PubMed Web of Science ®Google Scholar
• Smith MA, Drew KL, Nunomura A et al. Amyloid-β, tau alterations and mitochondrial dysfunction in Alzheimer disease: the chickens or the eggs? Neurochem. Int.40(6), 527–531 (2002).
   PubMedGoogle Scholar
• Yates CM, Butterworth J, Tennant MC, Gordon A. Enzyme activities in relation to pH and lactate in postmortem brain in Alzheimer-type and other dementias. J. Neurochem.55(5), 1624–1630 (1990).
   PubMed Web of Science ®Google Scholar
• Mastrogiacomo F, Bergeron C, Kish SJ. Brain α-ketoglutarate dehydrogenase complex activity in Alzheimer’s disease. J. Neurochem.61(6), 2007–2014 (1993).
   PubMed Web of Science ®Google Scholar
• Simonian NA, Hyman BT. Functional alterations in Alzheimer’s disease: selective loss of mitochondrial-encoded cytochrome oxidase mRNA in the hippocampal formation. J. Neuropathol. Exp. Neurol.53(5), 508–512 (1994).
   PubMed Web of Science ®Google Scholar
• Perry G, Sayre LM, Atwood CS et al. The role of iron and copper in the aetiology of neurodegenerative disorders: therapeutic implications. CNS Drugs16(5), 339–352 (2002).
   PubMed Web of Science ®Google Scholar
• Smith MA, Harris PL, Sayre LM, Perry G. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc. Natl Acad. Sci. USA94(18), 9866–9868 (1997).
   PubMed Web of Science ®Google Scholar
• Sayre LM, Perry G, Harris PL et al.In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer’s disease: a central role for bound transition metals. J. Neurochem.74(1), 270–279 (2000).
   PubMed Web of Science ®Google Scholar
• Honda K, Smith MA, Zhu X et al. Ribosomal RNA in Alzheimer disease is oxidized by bound redox-active iron. J. Biol. Chem.280(22), 20978–20986 (2005).
   PubMed Web of Science ®Google Scholar
• Bush AI, Multhaup G, Moir RD et al. A novel zinc(II) binding site modulates the function of the β A4 amyloid protein precursor of Alzheimer’s disease. J. Biol. Chem.268(22), 16109–16112 (1993).
   PubMed Web of Science ®Google Scholar
• Bush AI, Pettingell WH, Multhaup G et al. Rapid induction of Alzheimer A β amyloid formation by zinc. Science265(5177), 1464–1467 (1994).
   PubMed Web of Science ®Google Scholar
• Multhaup G, Bush AI, Pollwein P, Masters CL. Interaction between the zinc (II) and the heparin binding site of the Alzheimer’s disease β A4 amyloid precursor protein (APP). FEBS Lett.355(2), 151–154 (1994).
   PubMed Web of Science ®Google Scholar
• Huang X, Atwood CS, Moir RD et al. Zinc-induced Alzheimer’s Aβ1-40 aggregation is mediated by conformational factors. J. Biol. Chem.272(42), 26464–26470 (1997).
   PubMed Web of Science ®Google Scholar
• Cuajungco MP, Faget KY, Huang X, Tanzi RE, Bush AI. Metal chelation as a potential therapy for Alzheimer’s disease. Ann. NY Acad. Sci.920, 292–304 (2000).
   PubMed Web of Science ®Google Scholar
• Liu G, Garrett MR, Men P et al. Nanoparticle and other metal chelation therapeutics in Alzheimer disease. Biochim. Biophys. Acta1741(3), 246–252 (2005).
   PubMed Web of Science ®Google Scholar
• Panayi AE, Spyrou NM, Iversen BS, White MA, Part P. Determination of cadmium and zinc in Alzheimer’s brain tissue using inductively coupled plasma mass spectrometry. J. Neurol. Sci.195(1), 1–10 (2002).
   PubMed Web of Science ®Google Scholar
• Bondy SC, Guo-Ross SX, Truong AT. Promotion of transition metal-induced reactive oxygen species formation by β-amyloid. Brain Res.799(1), 91–96 (1998).
   PubMed Web of Science ®Google Scholar
• Huang X, Atwood CS, Hartshorn MA et al. The A β peptide of Alzheimer’s disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry (Mosc.)38(24), 7609–7616 (1999).
   Google Scholar
• Burton GW, Joyce A, Ingold KU. First proof that vitamin E is major lipid-soluble, chain-breaking antioxidant in human blood plasma. Lancet2(8293), 327 (1982).
   PubMed Web of Science ®Google Scholar
• Jama JW, Launer LJ, Witteman JC et al. Dietary antioxidants and cognitive function in a population-based sample of older persons. The Rotterdam Study. Am. J. Epidemiol.144(3), 275–280 (1996).
   PubMed Web of Science ®Google Scholar
• Perrig WJ, Perrig P, Stahelin HB. The relation between antioxidants and memory performance in the old and very old. J. Am. Geriatr. Soc.45(6), 718–724 (1997).
   PubMed Web of Science ®Google Scholar
• Zandi PP, Anthony JC, Khachaturian AS et al. Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. Arch. Neurol.61(1), 82–88 (2004).
   PubMed Web of Science ®Google Scholar
• Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch. Neurol.57(10), 1439–1443 (2000).
   PubMed Web of Science ®Google Scholar
• Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet356(9242), 1627–1631 (2000).
   PubMed Web of Science ®Google Scholar
• Simons M, Keller P, De Strooper B et al. Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons. Proc. Natl Acad. Sci. USA95(11), 6460–6464 (1998).
   PubMed Web of Science ®Google Scholar
• Li L, Cao D, Kim H, Lester R, Fukuchi K. Simvastatin enhances learning and memory independent of amyloid load in mice. Ann. Neurol.60(6), 729–739 (2006).
   Google Scholar
• McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: a review of 17 epidemiologic studies. Neurology47(2), 425–432 (1996).
   PubMed Web of Science ®Google Scholar
• in t’ Veld BA, Ruitenberg A, Hofman A et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N. Engl. J. Med.345(21), 1515–1521 (2001).
   PubMed Web of Science ®Google Scholar
• Cagnin A, Brooks DJ, Kennedy AM et al.In vivo measurement of activated microglia in dementia. Lancet358(9280), 461–467 (2001).
   PubMed Web of Science ®Google Scholar
• Nandoe RD, Scheltens P, Eikelenboom P. Head trauma and Alzheimer’s disease. J. Alzheimers Dis.4(4), 303–308 (2002).
   PubMed Web of Science ®Google Scholar
• Rogers J, Cooper NR, Webster S et al. Complement activation by β-amyloid in Alzheimer disease. Proc. Natl Acad. Sci. USA89(21), 10016–10020 (1992).
   PubMed Web of Science ®Google Scholar
• Griffin WS, Stanley LC, Ling C et al. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc. Natl Acad. Sci. USA86(19), 7611–7615 (1989).
   PubMed Web of Science ®Google Scholar
• Dickson DW, Lee SC, Mattiace LA, Yen SH, Brosnan C. Microglia and cytokines in neurological disease, with special reference to AIDS and Alzheimer’s disease. Glia7(1), 75–83 (1993).
   PubMed Web of Science ®Google Scholar
• Akiyama H, Barger S, Barnum S et al. Inflammation and Alzheimer’s disease. Neurobiol. Aging21(3), 383–421 (2000).
   PubMed Web of Science ®Google Scholar
• Breitner JC, Gau BA, Welsh KA et al. Inverse association of anti-inflammatory treatments and Alzheimer’s disease: initial results of a co-twin control study. Neurology44(2), 227–232 (1994).
   PubMed Web of Science ®Google Scholar
• Breitner JC, Welsh KA, Helms MJ et al. Delayed onset of Alzheimer’s disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Neurobiol. Aging16(4), 523–530 (1995).
   PubMed Web of Science ®Google Scholar
• Anthony JC, Breitner JC, Zandi PP et al. Reduced prevalence of AD in users of NSAIDs and H2 receptor antagonists: the Cache County study. Neurology54(11), 2066–2071 (2000).
   PubMed Web of Science ®Google Scholar
• The Canadian Study of Health and Aging: risk factors for Alzheimer’s disease in Canada. Neurology44(11), 2073–2080 (1994).
   PubMed Web of Science ®Google Scholar
• Beard CM, Waring SC, O’Brien PC, Kurland LT, Kokmen E. Nonsteroidal anti-inflammatory drug use and Alzheimer’s disease: a case-control study in Rochester, Minnesota, 1980 through 1984. Mayo Clin. Proc.73(10), 951–955 (1998).
   PubMed Web of Science ®Google Scholar
• Launer L. Nonsteroidal anti-inflammatory drug use and the risk for Alzheimer’s disease: dissecting the epidemiological evidence. Drugs63(8), 731–739 (2003).
   PubMedGoogle Scholar
• Jorm AF, Jolley D. The incidence of dementia: a meta-analysis. Neurology51(3), 728–733 (1998).
   PubMed Web of Science ®Google Scholar
• Tang MX, Jacobs D, Stern Y et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet348(9025), 429–432 (1996).
   PubMed Web of Science ®Google Scholar
• Manly JJ, Merchant CA, Jacobs DM et al. Endogenous estrogen levels and Alzheimer’s disease among postmenopausal women. Neurology54(4), 833–837 (2000).
   PubMed Web of Science ®Google Scholar
• Shumaker SA, Legault C, Rapp SR et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA289(20), 2651–2662 (2003).
   PubMed Web of Science ®Google Scholar
• Zhu X, Raina AK, Smith MA. Cell cycle events in neurons. Proliferation or death? Am. J. Pathol.155(2), 327–329 (1999).
   PubMed Web of Science ®Google Scholar
• Raina AK, Zhu X, Rottkamp CA et al. Cyclin’ toward dementia: cell cycle abnormalities and abortive oncogenesis in Alzheimer disease. J. Neurosci. Res.61(2), 128–133 (2000).
   PubMed Web of Science ®Google Scholar
• Raina AK, Zhu X, Smith MA. Alzheimer’s disease and the cell cycle. Acta Neurobiol. Exp. (Wars.)64(1), 107–112 (2004).
   PubMedGoogle Scholar
• Casadesus G, Zhu X, Atwood CS et al. Beyond estrogen: targeting gonadotropin hormones in the treatment of Alzheimer’s disease. Curr. Drug Targets3(4), 281–285 (2004).
   Google Scholar
• Webber KM, Casadesus G, Marlatt MW et al. Estrogen bows to a new master: the role of gonadotropins in Alzheimer pathogenesis. Ann. NY Acad. Sci.1052, 201–209 (2005).
   PubMedGoogle Scholar
• Kopke E, Tung YC, Shaikh S et al. Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J. Biol. Chem.268(32), 24374–24384 (1993).
   PubMed Web of Science ®Google Scholar
• Alonso AC, Grundke-Iqbal I, Iqbal K. Alzheimer’s disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat. Med.2(7), 783–787 (1996).
   PubMed Web of Science ®Google Scholar
• Alonso AD, Grundke-Iqbal I, Barra HS, Iqbal K. Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau. Proc. Natl Acad. Sci. USA94(1), 298–303 (1997).
   PubMed Web of Science ®Google Scholar
• Iqbal K, Alonso AD, Gondal JA et al. Mechanism of neurofibrillary degeneration and pharmacologic therapeutic approach. J. Neural Transm. Suppl.59, 213–222 (2000).
   Google Scholar
• Gong CX, Shaikh S, Wang JZ et al. Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain. J. Neurochem.65(2), 732–738 (1995).
   PubMed Web of Science ®Google Scholar
• Wang JZ, Grundke-Iqbal I, Iqbal K. Restoration of biological activity of Alzheimer abnormally phosphorylated tau by dephosphorylation with protein phosphatase-2A, -2B and -1. Brain Res. Mol. Brain Res.38(2), 200–208 (1996).
   PubMedGoogle Scholar
• Oliver CJ, Shenolikar S. Physiologic importance of protein phosphatase inhibitors. Front. Biosci.3, D961–D972 (1998).
   PubMedGoogle Scholar
• Gong CX, Singh TJ, Grundke-Iqbal I, Iqbal K. Phosphoprotein phosphatase activities in Alzheimer disease brain. J. Neurochem.61(3), 921–927 (1993).
   PubMed Web of Science ®Google Scholar
• Iqbal K, Alonso Adel C, El-Akkad E et al. Alzheimer neurofibrillary degeneration: therapeutic targets and high-throughput assays. J. Mol. Neurosci.20(3), 425–429 (2003).
   PubMedGoogle Scholar
• Cash AD, Aliev G, Siedlak SL et al. Microtubule reduction in Alzheimer’s disease and aging is independent of tau filament formation. Am. J. Pathol.162(5), 1623–1627 (2003).
   PubMed Web of Science ®Google Scholar
• Nunomura A, Perry G, Aliev G et al. Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol.60(8), 759–767 (2001).
   PubMed Web of Science ®Google Scholar
• Nunomura A, Perry G, Pappolla MA et al. RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer’s disease. J. Neurosci.19(6), 1959–1964 (1999).
   PubMed Web of Science ®Google Scholar
• Terry RD, Masliah E, Salmon DP et al. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol.30(4), 572–580 (1991).
   PubMed Web of Science ®Google Scholar
• Wenk GL, Danysz W, Roice DD. The effects of mitochondrial failure upon cholinergic toxicity in the nucleus basalis. Neuroreport7(9), 1453–1456 (1996).
   PubMed Web of Science ®Google Scholar
• Zajaczkowski W, Quack G, Danysz W. Infusion of (+)-MK-801 and memantine – contrasting effects on radial maze learning in rats with entorhinal cortex lesion. Eur. J. Pharmacol.296(3), 239–246 (1996).
   PubMed Web of Science ®Google Scholar
• Zajaczkowski W, Frankiewicz T, Parsons CG, Danysz W. Uncompetitive NMDA receptor antagonists attenuate NMDA-induced impairment of passive avoidance learning and LTP. Neuropharmacology36(7), 961–971 (1997).
   PubMed Web of Science ®Google Scholar
• Braak H, Braak E. Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol. Aging16(3), 271–278; discussion 278–284 (1995).
   PubMed Web of Science ®Google Scholar
• Bussiere T, Giannakopoulos P, Bouras C et al. Progressive degeneration of nonphosphorylated neurofilament protein-enriched pyramidal neurons predicts cognitive impairment in Alzheimer’s disease: stereologic analysis of prefrontal cortex area 9. J. Comp. Neurol.463(3), 281–302 (2003).
   PubMed Web of Science ®Google Scholar
• Bouvier M, Szatkowski M, Amato A, Attwell D. The glial cell glutamate uptake carrier countertransports pH-changing anions. Nature360(6403), 471–474 (1992).
   PubMed Web of Science ®Google Scholar
• Clements JD, Lester RA, Tong G, Jahr CE, Westbrook GL. The time course of glutamate in the synaptic cleft. Science258(5087), 1498–1501 (1992).
   PubMedGoogle Scholar
• Danbolt NC. Glutamate uptake. Prog. Neurobiol.65(1), 1–105 (2001).
   PubMed Web of Science ®Google Scholar
• Koh JY, Choi DW. Selective blockade of non-NMDA receptors does not block rapidly triggered glutamate-induced neuronal death. Brain Res.548(1–2), 318–321 (1991).
   PubMedGoogle Scholar
• Castegna A, Aksenov M, Aksenova M et al. Proteomic identification of oxidatively modified proteins in Alzheimer’s disease brain. Part I: creatine kinase BB, glutamine synthase, and ubiquitin carboxy-terminal hydrolase l-1. Free Radic. Biol. Med.33(4), 562–571 (2002).
   PubMed Web of Science ®Google Scholar
• Hensley K, Hall N, Subramaniam R et al. Brain regional correspondence between Alzheimer’s disease histopathology and biomarkers of protein oxidation. J. Neurochem.65(5), 2146–2156 (1995).
   PubMed Web of Science ®Google Scholar
• Kornhuber J, Bormann J, Retz W, Hubers M, Riederer P. Memantine displaces [3H]MK-801 at therapeutic concentrations in postmortem human frontal cortex. Eur. J. Pharmacol.166(3), 589–590 (1989).
   PubMed Web of Science ®Google Scholar
• Parsons CG, Gruner R, Rozental J, Millar J, Lodge D. Patch clamp studies on the kinetics and selectivity of N-methyl-D-aspartate receptor antagonism by memantine (1-amino-3,5-dimethyladamantan). Neuropharmacology32(12), 1337–1350 (1993).
   PubMed Web of Science ®Google Scholar
• Misztal M, Frankiewicz T, Parsons CG, Danysz W. Learning deficits induced by chronic intraventricular infusion of quinolinic acid – protection by MK-801 and memantine. Eur. J. Pharmacol.296(1), 1–8 (1996).
   PubMed Web of Science ®Google Scholar
• Ditzler K. Efficacy and tolerability of memantine in patients with dementia syndrome. A double-blind, placebo controlled trial. Arzneimittelforschung41(8), 773–780 (1991).
   PubMed Web of Science ®Google Scholar
• Gortelmeyer R, Erbler H. Memantine in the treatment of mild to moderate dementia syndrome. A double-blind placebo-controlled study. Arzneimittelforschung42(7), 904–913 (1992).
   PubMed Web of Science ®Google Scholar
• Winblad B, Poritis N. Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine). Int. J. Geriatr. Psychiatry14(2), 135–146 (1999).
   PubMed Web of Science ®Google Scholar
• Kasa P, Rakonczay Z, Gulya K. The cholinergic system in Alzheimer’s disease. Prog. Neurobiol.52(6), 511–535 (1997).
   PubMed Web of Science ®Google Scholar
• Sims NR, Bowen DM, Allen SJ et al. Presynaptic cholinergic dysfunction in patients with dementia. J. Neurochem.40(2), 503–509 (1983).
   PubMed Web of Science ®Google Scholar
• DeKosky ST, Harbaugh RE, Schmitt FA et al. Cortical biopsy in Alzheimer’s disease: diagnostic accuracy and neurochemical, neuropathological and cognitive correlations. Intraventricular Bethanecol Study Group. Ann. Neurol.32(5), 625–632 (1992).
   PubMed Web of Science ®Google Scholar
• Whitehouse PJ. Cholinergic therapy in dementia. Acta Neurol. Scand.149(Suppl.), 42–45 (1993).
   Google Scholar
• Giacobini E. Cholinesterase inhibitors stabilize Alzheimer’s disease. Ann. NY Acad. Sci.920, 321–327 (2000).
   PubMed Web of Science ®Google Scholar
• Giacobini E. Do cholinesterase inhibitors have disease-modifying effects in Alzheimer’s disease? CNS Drugs15(2), 85–91 (2001).
   PubMed Web of Science ®Google Scholar
• Giacobini E. Long-term stabilizing effect of cholinesterase inhibitors in the therapy of Alzheimer’ disease. J. Neural Transm. Suppl.(62), 181–187 (2002).
   Google Scholar
• Racchi M, Mazzucchelli M, Porrello E, Lanni C, Govoni S. Acetylcholinesterase inhibitors: novel activities of old molecules. Pharmacol. Res.50(4), 441–451 (2004).
   PubMed Web of Science ®Google Scholar
• Meyer JS, Li Y, Xu G et al. Feasibility of treating mild cognitive impairment with cholinesterase inhibitors. Int. J. Geriatr. Psychiatry17(6), 586–588 (2002).
   PubMed Web of Science ®Google Scholar
• Giacobini E. Cholinesterase inhibitors: new roles and therapeutic alternatives. Pharmacol. Res.50(4), 433–440 (2004).
   PubMed Web of Science ®Google Scholar
• Mori F, Lai CC, Fusi F, Giacobini E. Cholinesterase inhibitors increase secretion of APPs in rat brain cortex. Neuroreport6(4), 633–636 (1995).
   PubMed Web of Science ®Google Scholar
• Giacobini E, Mori F, Lai CC. The effect of cholinesterase inhibitors on the secretion of APPS from rat brain cortex. Ann. NY Acad. Sci.777, 393–398 (1996).
   PubMedGoogle Scholar
• Tuszynski MH. Growth-factor gene therapy for neurodegenerative disorders. Lancet Neurol.1(1), 51–57 (2002).
   PubMed Web of Science ®Google Scholar
• Savage MJ, Lin YG, Ciallella JR, Flood DG, Scott RW. Activation of c-Jun N-terminal kinase and p38 in an Alzheimer’s disease model is associated with amyloid deposition. J. Neurosci.22(9), 3376–3385 (2002).
   PubMed Web of Science ®Google Scholar
• Rabizadeh S, Bredesen DE. Ten years on: mediation of cell death by the common neurotrophin receptor p75(NTR). Cytokine Growth Factor Rev.14(3–4), 225–239 (2003).
   PubMedGoogle Scholar
• Zhu X, Raina AK, Rottkamp CA et al. Activation and redistribution of c-jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer’s disease. J. Neurochem.76(2), 435–441 (2001).
   PubMed Web of Science ®Google Scholar
• Yaar M, Zhai S, Fine RE et al. Amyloid β binds trimers as well as monomers of the 75-kDa neurotrophin receptor and activates receptor signaling. J. Biol. Chem.277(10), 7720–7725 (2002).
   PubMed Web of Science ®Google Scholar
• Lee R, Kermani P, Teng KK, Hempstead BL. Regulation of cell survival by secreted proneurotrophins. Science294(5548), 1945–1948 (2001).
   PubMed Web of Science ®Google Scholar
• Fahnestock M, Michalski B, Xu B, Coughlin MD. The precursor pro-nerve growth factor is the predominant form of nerve growth factor in brain and is increased in Alzheimer’s disease. Mol. Cell. Neurosci.18(2), 210–220 (2001).
   PubMed Web of Science ®Google Scholar
• Poduslo JF, Curran GL. Permeability at the blood–brain and blood–nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF. Brain Res. Mol. Brain Res.36(2), 280–286 (1996).
   PubMedGoogle Scholar
• Hempstead BL. The many faces of p75NTR. Curr. Opin. Neurobiol.12(3), 260–267 (2002).
   PubMed Web of Science ®Google Scholar
• Longo FM, Manthorpe M, Xie YM, Varon S. Synthetic NGF peptide derivatives prevent neuronal death via a p75 receptor-dependent mechanism. J. Neurosci. Res.48(1), 1–17 (1997).
   PubMedGoogle Scholar
• Xie Y, Tisi MA, Yeo TT, Longo FM. Nerve growth factor (NGF) loop 4 dimeric mimetics activate ERK and AKT and promote NGF-like neurotrophic effects. J. Biol. Chem.275(38), 29868–29874 (2000).
   PubMedGoogle Scholar
• Maliartchouk S, Debeir T, Beglova N et al. Genuine monovalent ligands of TrkA nerve growth factor receptors reveal a novel pharmacological mechanism of action. J. Biol. Chem.275(14), 9946–9956 (2000).
   PubMedGoogle Scholar
• DeFreitas MF, McQuillen PS, Shatz CJ. A novel p75NTR signaling pathway promotes survival, not death, of immunopurified neocortical subplate neurons. J. Neurosci.21(14), 5121–5129 (2001).
   PubMedGoogle Scholar
• Khursigara G, Bertin J, Yano H et al. A prosurvival function for the p75 receptor death domain mediated via the caspase recruitment domain receptor-interacting protein 2. J. Neurosci.21(16), 5854–5863 (2001).
   PubMedGoogle Scholar
• Mamidipudi V, Wooten MW. Dual role for p75(NTR) signaling in survival and cell death: can intracellular mediators provide an explanation? J. Neurosci. Res.68(4), 373–384 (2002).
   PubMed Web of Science ®Google Scholar
• Dobrowsky RT, Carter BD. p75 neurotrophin receptor signaling: mechanisms for neurotrophic modulation of cell stress? J. Neurosci. Res.61(3), 237–243 (2000).
   PubMedGoogle Scholar
• McShea A, Harris PL, Webster KR, Wahl AF, Smith MA. Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer’s disease. Am. J. Pathol.150(6), 1933–1939 (1997).
   PubMed Web of Science ®Google Scholar
• Ogawa O, Lee HG, Zhu X et al. Increased p27, an essential component of cell cycle control, in Alzheimer’s disease. Aging Cell2(2), 105–110 (2003).
   PubMed Web of Science ®Google Scholar
• Ogawa O, Zhu X, Lee HG et al. Ectopic localization of phosphorylated histone H3 in Alzheimer’s disease: a mitotic catastrophe? Acta Neuropathol. (Berl.)105(5), 524–528 (2003).
   PubMed Web of Science ®Google Scholar
• Woods J, Snape M, Smith MA. The cell cycle hypothesis of Alzheimer’s disease: suggestions for drug development. Biochim. Biophys. Acta1772(4), 503–508 (2007).
   PubMed Web of Science ®Google Scholar
• McShea A, Lee HG, Casadesus G et al. Neuronal cell cycle reentry mediates Alzheimer-type changes. Biochim. Biophys. Acta.1772(4), 467–472 (2007).
   PubMed Web of Science ®Google Scholar
• Marlatt MW, Webber KM, Moreira PI et al. Therapeutic opportunities in Alzheimer disease: one for all or all for one? Curr. Med. Chem.12(10), 1137–1147 (2005).
   PubMed Web of Science ®Google Scholar