APLICACIONES DE LA TEORÍA DE JUEGOS (TDJ)

One anticholinesterase, tetrahydroaminoacridine (THA, tacrine, "Cognex"), has passed the Food and Drug Administration's licensing procedures for use in treating mild to m oderate AD. It has also been approved by the authorities in France. However, studies have been equally divided between those reporting benefit for some patients, and those reporting no benefit (Bryne and Arie, 1994). The dose of tacrine varies considerably between studies, and most report high levels of hepatotoxicity and cholinergic side effects. Also, most studies used too few patients to provide the power to prove or disprove the hypothesis. Well designed trials with adequate numbers of subjects have shown that tacrine benefits some patients, and thebenefitsare expressed either as improvement in the core deficits of AD, or as reduced rate of deterioration (Davis et a l , 1992). However, only very few patients benefit greatly. This may be due to many reasons: the dose may be inadequate; larger doses are commonly associated with more side effects and incidence of toxicity, with resultant withdrawal of the subject from the study; also, positive diagnosis of AD cannot be absolute in life: it is likely that a number of patients included in a trial may be suffering from other forms of dementia.

While it is clear that tacrine is not an ideal anticholinesterase inhibitor, with high incidence of toxicity and short duration of action, the results of some trials are encouraging. It is hoped that the next generation of anticholinesterase inhibitors will address these problems (Giacobini et a l, 1991). Thus it may be premature and pessimistic to dismiss cholinergic replacement therapy at present, in view of the limitations of available cholinomimetics. In the future, it may transpire that the most effective treatments for AD require polypharmacy. There is substantial evidence that in addition to the cholinergic system, other neurotransmitter systems are impaired in AD, and many believe that these deficiencies attenuate the potential response to cholinergic drugs (Davis and Haroutunian, 1992). Therefore treating several neurotransmitter deficiencies at the same time may enhance the effectiveness of cholinomimetics at lower doses.

The rationale for polypharmacy as a long term therapeutic strategy for AD is compelling: for example, combining growth-promoting compounds designed to prevent synaptic loss or cell death with compounds designed to restore neurotransmitter deficits.

However, polypharmacy also presents difficult methodological problems from the perspective of designing clinical trials and determining efficacy.

8 .5 THE FUTURE

Promising transmitter-related drugs (cholinomimetics and S-HTi^ receptor antagonists) that may improve cognitive symptoms in AD and should also beneficially affect the metabolism of APP by favouring non-amyloidogenic processing are under development by the pharmaceutical industry.

Results in Chapters 3 and 7 seem to show that APP^pi may be less abundant than APLP2 in human cortical membranes. (For example, note that the intense band running just ahead of marker 116 in lane 1 of Fig. 7.1 C is apparently only weakly visualised in lanes 15-19 of Fig 3.1). It remains to be established whether the processing of this apparently abundant KPI-containing protein of human brain cortical membranes is stimulated (like APP) by depolarisation and receptor-linked protein phosphorylation (an important issue as the protein should carry out many of the functions of APP without producing 6/A4). The preparation of the monoclonal antibody to APLP2 (see Chapter 7) is the starting point for a detailed study of this type. Other investigations that need to be carried out, using this novel antibody, include those to discover whether changes reported using non-specific APP antibodies (e.g. 22C11) reflect a change in APLP2 rather than in APP.

It is important to discover any effect of these transmitter-related drugs on the signal-transduction-dependent phosphorylation and dephosphorylation of tau protein, in particular, on the aberrant mechanism that leads to the hyperphosphorylation of tau and almost certainly underlies NFT formation, the other pathological hallmark of AD. Such hyperphosphorylation characteristically occurs in the pyramidal neurones and further research is required to provide more compelling support for the theory (based on the hypothesis that hypoactivity of glutamatergic neurones underlies the symptoms of AD; see Francis et a l , 1993b) that the number of tangles, like plaques and cognitive impairment, will be reduced by a drug/drugs designed to improve the state of pyramidal neurone activation.

It is by no means certain that such drug(s) will attain therapeutic goals (e.g. delay onset of institutionalisation of patients by extending their ability to function independently). However, a positive outcome is now not inconceivable and treatment

strategies proposed in this thesis (see 8.3) could have a favourable impact on the burden of AD.

REFERENCES

Abe, K,, StGeorge-Hyslop, P.H., Tanzi, R.E. and Kogure, K. (1991a) Induction of amyloid precursor protein mRNA after heat shock in cultured human lymphoblastoid cells, Neurosci. Lett., 125:169-171.

Abe, K., Tanzi, R.E. and Kogure, K. (1991b) Selective induction of kunitz-type pro tea se inhibitor domain-containing amyloid precursor protein mRNA after persistant focal ischemia in rat cerebral cortex, Neurosci. Lett., 125: 172-174.

Abraham, C.R., Selkoe, D.J. and Potter, H. (1988) Immunochemical identification of the serine protease inhibitor al-antichymotrypsin in the brain amyloid deposits of Alzheimer’s disease. Cell, 52: 487-501.

Abraham, C.R., Driscoll, J., Potter, H., Van Nostrand, W.E. and Tempst, P. (1991) A calcium-activated protease from Alzheimer’s disease brain cleaves at the N-terminus of the amyloid ft-protein, Biochem. Biophys. Res. Comm., 174: 790-796.

Adolfsson, R., Gottfries, C.G., Roos, B.E. and Winblad, B. (1979) Changes in brain catecholamines in patients with dementia of Alzheimer type, Br. J. Psychiat, 135: 216-223.

Aigner, T.G., Mitchell, S.J., Aggleton, J.P., De Long, M.R., Struble, R.G., Price, D.L., Wenk, G.L and Mishkin, M. (1987) Effects of scopolamine and physostigmine on recognition memory in monkeys with ibotinic-acid lesions of the nucleus basalis of Meynert, Psychopharmacology, 92: 292-300.

Akiyama, H., McGeer, P.L., Itagaki, S., McGeer, E.G. and Kaneko, T. (1989) Loss of glutaminase-positive cortical neurons in Alzheimer’s disease, Neurochem. Res., 14: 353-358.

Alkon, D.L, Amaral, D.G., Bear, M.F., Black, J., Carew, T.J., Cohen, N.J., Disterhoft, J.F., Eichenbaum, H., Golski, S., Gorman, L.K., Lynch, G., McNaugton, B.L., Mishkin, M., Moyer, J.R., Olds, J.L., Olton, D,S., Otto, T., Squire, L.R., Staubli, U., Thompson, L.T. and "Wible, C. (1991) Learning and memory, Br. Res. Rev., 16:193-220.

Allison, J.H., Blisner, M.E., Holland, W.H., Hipps, P.P. and Sherman, W.R. (1976) Increased brain wyMnositol 1-phosphate in lithium-treated rats, Biochem. Biophys. Res. Comm., 71: 664-670.

Allison, J.H. and Stewart, M.A. (1971) Reduced brain inositol in lithium-treated rats. Nature, 233: 267-268.

Alzheimer’s Disease and Related Disorders Association, (1992) Statistical data on Alzheimer’s disease, Chicago,

Alzheimer, A. (1907) Uber eine eigenartige Erkrankung der Himrinde, Allgemeine Zeitschrift fur Psychiatrie und Psychisch-Gerichtlich Medicin, 64:146-148.

American Psychiatric Association, (1980) Diagnostic and statistical manual of mental disorders, APA, Washington, DC,

American Psychiatric Association, (1987) Diagnostic and statistical manual of mental disorders, 3rd edn., Washington, DC,

Anderson, J.P., Chen, Y.U., Kim, K.S. and Robakis, N.K. (1992) An alternative secretase cleavage produces soluble Alzheimer amyloid precursor protein containing a potentially amyloidogenic sequence, J. Neurochem., 59: 2328-2331.

Anglister, LI., Farber, I.C., Sharar, A and Grinvald, A (1982) Localisation of voltage sensitive calcium channels along developing neurites: their possible role in regulation of neurite elongation, Dev. Biol., 94: 351-365.

Arai, H., Kosaka, K. and lizuka, R. (1984a) Changes of biogenic amines and their metabolites in post-mortem brains from patients with Azheimer-type dementia, J. Neurochem., 43: 388-393.

Arai, H., Moroji, T. and Kosaka, K. (1984b) Somatostatin and vasoactive intestinal polypeptide in post-mortem brains from patients with Azheimer-type dementia, Neurosci. Lett., 52: 73-78.

Arai, H., Kobayashi, K., Ichimiya, Y., Kosaka, K. and lizuka, R. (1985) Free-amino acids in

postmortem cerebral cortices from patients with Azheimer-type dementia, Neurosci. Res., 2: 486-490.

A ai, H., Lee, V.M-Y., Messinger, M.L., Greenberg, B.D., Lowery, D.E. and Trojanowski, J.Q. (1991) Expression patterns of fi-amyloid precursor protein (E-APP) in neural and nonneural human tissues from AzheimePs disease and control subjects, Ann. Neurol., 30: 686-693.

Aendt, T., Bigl, V., Tennstedt, A and A endt, A (1985) Neuronal loss in different parts of the nucleus basalis is related to neuritic plaque formation in cortical target areas in AzheimePs Disease, Neuroscience, 14:1-14.

A s p e , N., Rojas, E. and Pollard, H.B. (1993) AzheimeFs disease amyloid fi protein forms calcium channels in bilayer membranes: Blockade by tromethamine and aluminium, Proc. Natl. Acad. Sci. USA, 90: 567-571.

Ashall, F. and Goate, AM. (1994) Role of 8-amyloid precursor protein in AzheimeFs disease, Trends Biochem. Sci., 19: 42-46.

Bahmanyar, S., Higgins, G.A, Goldgaber, D., Lewis, D.A, Morrison, J.H., Wilson, M.C., Shankar, S.K. and Gajdusek, D.C. (1987) Localisation of amyloid 8 protein messenger RNA in brains from patients with AzheimeFs disease. Science, 237: 77-80.

Baker, G.B. and Reynolds, G.P. (1989) Biogenic amines and their metabolites in AzheimeFs disease: noradrenaline, 5-hydroxytryptamine and 5-hydroxyindole-3-acetic acid depleted in hippocampus but not in substantia innominata, Neurosci. Lett., 100: 335-339.

Bareggi, S.R., Francceshi, M., Bonini, L, Zecca, L. and Smime, S. (1982) Decreased CSF concentrations of HVA and G ABA in AzheimeFs disease. Arch. Neurol, 39: 709-712.

Bartus, R.T., Dean, R.L., Beer, B. and Lippa, AS. (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science, 217: 408-417,

Baskin, F., Rosenberg, R.N. and Greenberg, B.D. (1991) Increased release of an amyloidogenic C-terminal Azheimer precursor protein fragment from stressed PC-12 cells, J. Neurosci. Res., 29:127-132.

Beach, T.G., Walker, R. and McGeer, E.G. (1989) Patterns of gliosis in AzheimePs disease and aging cerebrum, GLIA 2: 420-436.

Beal, M.F. and Mazurek, M.F. (1987) Substance P-like immunoreactivity is reduced in AzheimeFs disease cerebral cortex. Neurology, 37:1205-1209.

Behl, C., Davis, J., Cole, G.M. and Schubert, D. (1992) Vitamin E protects nerve cells from amyloid 8 protein toxicity, Biochem. Biophys. Res. Comm., 186: 944-950.

Benson, D.F., Kuhl, D.E., Phelps, M.E., Cummings, J.L and Tsai, S.Y. (1983) The fluorodeoxy glucose 18F scan in Alzheimer and multi-infarct dementia. Arch. Neurol, 40: 711-714.

Berridge, M.J., Downes, C.P. and Hanley, M.R. (1989) Neural and developmental actions of lithium: a unifying hypothesis. Cell, 53: 411-419.

Bird, E.D., Gale, J.S. and Spokes, E.G.S. (1977) Huntington’s Chorea: postmortem activity of enzymes involved in cerebral glucose metabolism, J. Neurochem., 29: 539-545.

Blass, J.P., Baker, A.C., Ko, L.-W. and Black, R.S. (1990) Induction of Alzheimer antigens by an uncoupler of oxidative phosphorylation. Arch. Neurol, 47: 864-869.

Blessed, G,, Tomlinson, B.E. and Roth, M. (1968) The association between quantitative measures of dementia and senile changes in the cerebral grey matter of elderly subjects, Br. J. Psychiat., 144: 797-811.

Bomsel, M. and Mostov, K. (1992) Role of heterotrimeric G proteins in membrane traffic. Mol. Biol. Cell, 3:1317-1328.

Bondareff, W., Mountjoy, C.Q. and Roth, M. (1981) Selective loss of neurones of origin of adrenergic projection to cerebral cortex in senile dementia. Lancet, i: 783-784.

Bowen, D.M., Smith, C.B. and Davison, A.N. (1973) Molecular changes in senile dementia. Brain, 96: 849-856.

Bowen, D.M., Smith, C.B., White, P. and Davison, AN. (1976) Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain, 99: 459-496.

Bowen, D.M., Smith, C.B., White, P., Flack, R.H., Carrasco, L.H., Gedye, J.L. and Davison, AN. (1977) Chemical pathology of the organic dementias. II. Quantitative estimation of cellular changes in post-mortem brains. Brain, 100: 427-453.

Bowen, D.M., White, P., Spillane, J.A, Goodhardt, M.J., Curzon, G., Iwangoft P., Meier-Ruge, W. and Davison, AN. (1979) Accelerated ageing or selective neuronal loss as an important cause of dementia. Lancet, 1:11-14.

Bowen, D.M., Benton, J.S., Spillane, J.A, Smith, C.C.T. and Alen, S.J. (1982) Choline acetyltransferase activity and histopathology of frontal neocortex from biopsies of demented patients, J. Neurol. Sci., 57:191-202.

Bowen, D.M., Alen, S.J., Benton, J.S., Goodhardt, M.J., Haan, E.A, Palmer, AM., Sims, N.R., Smith, C.C.T., Spillane, J.A, Esiri, M.M., Neary, D., Snowden, J.S., Wilcock, G.K. and Davison, AN. (1983) Biochemical assessment of serotonergic and cholinergic dysfunction and cerebral atrophy in AzheimeFs disease, J. Neurochem., 41: 266-272.

Bowen, D.M., Francis, P.T., Sims, N.R. and Cross, AJ. (1992) Protection from Dementia, Science, 258: 1422-1423.

Bowen, D.M., Francis, P.T., Chessell, I.P. and Webster, M-T. (1994)

Neurotransmission-the link integrating Azheimer research? Trends. Neurosci., 17: 149-150.

Bowen, D.M., Francis, P.T., Chessell, I., Webster, M-T, Procter, AW., Chen, C.P.C-L, Qume, M., Neary, D., Cross, AJ. and Green, AR, (1995) AzheimeFs Disease: Is the improvement of cholinergic transmission the correct strategy? In N.R. Cuttler, C.G. Gottfries and K. Siegfried (Eds.), AzheimeFs disease: Clinical and treatment perspectives, John Wiley & Sons Ltd., pp. 89-116.

Bowling, A.C., Mutisya, E.M., Walker, L.C., Price, D.L, Cork, LG. and Beal, M.F. (1993) Age dependent impairment of mitochondrial function in primate brain, J. Neurochem., 60: 1964-1967.

Braak, H., Braak, E. and Kalus, P. (1989) Alzheimer’s disease: a real pathology and laminar pathology in the occipital isocortex, Acta Neuropathol., 77: 494-506.

Braak, H. and Braak, E. (1991) Neuropathological stageing of Alzheimer-related changes, Acta Neuropathol., 82: 239-259.

Brady, D.R. and Mufson, E.J. (1990) Amygdaloid pathology in Alzheimer’s

disease:qualitative and quantitative analysis. Dementia, 1: 5-17.

Brady, D.R. and Mufson, E.J. (1991) Alz-50 immunoreactive neuropil differentiates hippocampal complex subfields in Alzheimer’s disease, J. Comp. Neurol., 305: 489-507.

Breitner, J.C., Silverman, J.M., Mobs, R.C. and Davis, K.L (1988) Familial aggregation in Alzheimer’s disease: comparison of risk among relatives of early- and late-onset cases, and among male and female relatives in successive generations. Neurology, 38: 207-212.

Brion, J-P., Hanger, D.P., Couck, A-M. and Anderton, B.H. (1991) A68 proteins in Alzheimer’s disease are composed of several tau isoforms in a phosphorylated state which affects their electrophoretic mobilities, Biochem. J., 279: 831-836.

Brion, J-P., Smith, C., Couck, A-M., Gallo, J-M. and Anderton, B.H. (1993) Developmental changes in tau phosphorylation: Fetal tau is transiently phosphorylated in a manner similar to paired helical filament-tau characteristic of Alzheimer’s disease, J. Neurochem., 61: 2071-2080.

Brion, JP., Passareiro, H., Nunez, J. and Flament-Durand, J. (1985) Immunological detection of Tau protein in neurofibrillary tangles of Alzheimer’s disease, Arch. Biol, 95: 229-235.

Brittis, P.A., Canning, D.R. and Silver, J. (1992) Chondroitin sulfate as a regulator of neuronal patterning in the retina. Nature, 255: 733-736.

Brun, A. (1983) An overview of light and electron microscopic changes in Alzheimer’s disease, the standard reference. In B. Reisberg (Ed.),, Macmillan, New York, pp. 37-47.

Bryne, E. and Arie, T. (1994) Tetrahydroaminoacridine and Alzheimer’s disease, Br. Med. J., 868-869.

Burch, R.M. and Axelrod, J. (1987) Dissociation of bradykinin-induced prostaglandin formation from phosphatidylinositol turn-over in Swiss 3T3 fibroblasts:evidence for G-protein regulation of phospholipase A2, Proc. Natl. Acad. Sci. USA, 84: 6374-6378.

Burke, W.J., Park, D.H., Chung, H.D., Marshall, G.L., Haring, J.H. and Joh, T.H. (1990) Evidence for decreased transport of tryptophan hydroxylase in Azheimeris disease. Brain Res., 537: 83-87.

Bums, A , Jacoby, R. and Levy, R. (1990a) Psychiatric phenomena in Azheimeris disease. IV: Disorders of behaviour, Br. J. Psychiat, 157: 86-94.

Bums, A , Jacoby, R. and Levy, R. (1990b) Psychiatric phenomena in Azheimeris disease II: Disorders of perception, Br. J. Psychiat, 157: 76-81.

Busciglio, J., Lorenzo .A and Yankner, B.A (1992) Methodological variables in the assessment of beta amyloid neurotoxicity, Neurobiol. Aging, 13: 609-612.

Busciglio, J., Gabuzda, D.H., Matsudaira, P. and Yankner, B A (1993) Generation of B-amyloid in the secretory pathway in neuronal and non-neuronal cells, Proc. Natl. Acad. Sci. USA, 90; 2092-2096.

Busciglio, J., Lorenzo, A , Jeh, J. and Yankner, B.A (1995) B-amyloid fibrils induce tau phosphorylation and loss of microtubule binding. Neuron, 14: 879-888.

Bush, A , Multhaup, G. and Moir, R. (1994) A novel Zinc (II) binding site modulates the function of B/A4 amyloid protein precursor of AzheimePs disease, J. Biol. Chem., 268: 16109-16112.

Bush, AL, Martins, R.N., Rumble, B., Moir, R., Fuller, S., Milward, E., Currie, J., Ames, D., Weidemann, A , Fischer, P., Multhaup, G., Beyreuther, K. and Masters, C.L. (1990) The amyloid precursor of AzheimeFs disease is released by human platelets, J. Biol. Chem., 265: 15977-15983.

Butner, K.A and Kirschner, M.W. (1991) Tau protein binds to microtubules through a flexible array of distributed weak sites, J. Cell Biol., 115: 717-730.

Buxbaum, J.D., Gandy, S.E. and Cicchetti, P. (1990) Processing of Azheimer B/A4 amyloid precursor protein: Modulation by agents that regulate protein phosphorylation, Proc. Natl. Acad. Sci. USA, 87: 6003-6006.

Buxbaum, J.D., Oishi, M., Chen, H.I., Pinkas-Kramarski, P., Jaffe, E.A, Gandy, S.E. and Greengard, P. (1992) Cholinergic agonists and interleukin 1 regulate processing and secretion of the Azheimer B/A4 amyloid protein precursor, Proc. Natl. Acad. Sci. USA, 89: 10075-10078.

Buxbaum, J.D., Koo, E.H. and Greengard, P. (1993) Protein phosphorylation inhibits production of Alzheimer amyloid 8/A4 peptide, Proc. Natl. Acad. Sci. USA., 90: 9195-9198.

Cai, X-D., Golde, T.E. and Younkin, S.G. (1993) Release of excess amyloid E protein from a mutant amyloid E protein precursor. Science, 259: 514-516.

Cairns, N.J., Chadwick, A., Lantos, P.L., Levy, R. and Rossor, M.N. (1993) EA4 protein deposition in familial Alzheimer's disease with the mutation in codon 717 of the EA4 amyloid precursor protein gene and sporadic Alzheimer’s disease, Neurosci. Lett., 149: 137-140.

Candy, J.M., Gascoigne, A.D., Biggins, J.A, Smith, AL, Perry, R.H., Perry, E.K., McDermott, J.R. and Edwardson, J.A (1985) Somatostatin immunoreactivity in cortical and some subcortical regions in Azheimer Disease, J. Neurol. Sci., 71: 315-323.

Caporaso, G., Takei, K., Gandy, S., Matteoli, M., Munddigl, 0., Greengard, P. and De Camilli, P. (1994) Morphologic and biochemical analysis of the intracellular trafficking of the Azheimer E/A4 amyloid precursor protein, J. Neurosci., 14: 3122-3138.

Caporaso, G.L., Gandy, S.E., Buxbaum, J.D. and Greengard, P. (1992a) Chloroquine inhibits intracellular degradation but not secretion of Azheimer E/A4 amyloid precursor protein, Proc. Natl. Acad. Sci. USA, 89: 2252-2256.

Caporaso, G.L., Gandy, S.E., Buxbaum, J.D., Ramabhadran, T.V. and Greengard, P. (1992b) Protein phosphorylation regulates secretion of Azheimer E/A4 amyloid precursor protein, Proc. Natl. Acad. Sci. USA, 89: 3055-3059.

Carrell, R.W. (1988) AzheimePs disease: enter a protease inhibitor. Nature, 331: 478-479.

Chan-Palay, V. (1987) Somatostatin immunoreactive neurones in the human hippocampus and cortex shown by immunogold/silver intensification on vibratome sections: co-existance with neuropeptide Y neurones, and effects in Alzheimer-type dementia, J. Comp. Neurol, 260: 201-223.

Chartier-Harlin, M-C., Crawford, F., Houlden, H., Warren, A., Hughes, D., Fidani, L, Goate, A , Rossor, M., Roques, P., Hardy, J. and Mullan, M. (1991) Early onset Alzheimer’s disease caused by mutation at codon 717 of the 13-amyloid precursor protein gene, Nature, 353: 844-846.

Chase, T.N., Foster, N.L., Fedio, P., Brooks, R., Mansi, L. and Di Chiro, G. (1984) Regional