Neurotransmission—the link integrating Alzheimer research?

the original publication suggested PrPsc have not been found ~2. A that PrPsc was present) ~3, calling role for conformational differinto question the role this change ences is also problematical - it is (PrPc to PrPso) plays in patho- difficult to see how conformational differences could acgenesis. Our contention is that the commodate the number of nature of the agents causing un- scrapie strains and isolates that conventional slow infections is can be distinguished from each not established. In our view, the other following serial passages in key issue to be addressed is how a single P m - p genotype. For scrapie strains retain their distinc- example, in our own work we tive characteristics after multiple have demonstrated distinct difpassages in mice with the same ferences among three strains and Prn-p genotypes. These results five recent sheep isolates, all of indicate that there is a component which have been passaged at of the infectious agent that im- least three times in C57BL parts information that specifies mice 6'7'~4. The Edinburgh group, the characteristics of different using the same inbred mouse scrapie strains: for the virus hy- strain for serial passages, has pothesis6'7, this would be nucleic studied several additional strains acid with the capacity to code for that are distinguishable from the virus-specific proteins, and for the scrapie strains and isolates we virino hypothesis6'7, this would be have examined 2'3. a small, non-coding nucleic acid It is our firm view that the that uses host-specified protein nature of the agents causing un(perhaps PrP) as a protective coat, conventional slow infections and induces pathological changes remains one of the greatest by affecting regulatory mechan- puzzles in biology ~'~5. isms. The proponents of the prion hypothesis believe that differRichard L Carp ences in the PrP molecule (either Richard J. Kascsak post-translational modifications Richard Rubenstein or conformational differences) are Dept of Virology, NYS Institute for Basic capable of inducing the characResearch in Developmental Disabilities, 1050 teristics that distinguish scrapie ForestH#/ Road, StatenIsland, NY 19314, USA. strains and of maintaining these characteristics during serial Patricia A. Merz passages. They currently favor Dept of PathologicalNeurobto/ogy,NYSInstitute the conformational concept since for BasicResearchtn DevelopmentalDisab#ittes, post-translational modification 1050 ForestHi//Road, StatenIsland, NY 19314, differences between PrPc and USA.

References

Neu rotransmission - the link integrating Alzheimer research?

side effects compared with those receiving other medication (mostly antipsychotics). We have also reported that dementia, considered to be caused by hypoactivity of glutamatergic pyramidal neurones, is associated with reduced secretion and intracellular accumulation of APP, a proposal based on two observations. First, secreted APP is lower in the lumbar cerebrospinal fluid of demented patients with cortical pyramidal neurone loss compared with controls. This finding was independent of presynaptic cholinergic dysfunction and the presence of either senile plaques or neurofibrillary pathology. A plausible explanation for the presence of senile plaques in Alzheimer's

It is widely recognized that neurotransmitter replacement therapy is needed to ameliorate the cognitive impairment characteristic of AIzheimer's disease. Several groups, including our own ~'2, have provided evidence to support the idea outlined by Selkoe 3 that this approach will also beneficially affect the metabolism of the amyloid precursor protein (APP) by favouring the non-amyloidogenic pathway. Phosphorylation, stimulated by depolarization or second-messenger systems, might be enhanced by antagonists at the inhibitory TINS, Vol. 17, No. 4, 1994

5-HT1A receptor, or by activation of the phospholipase-C-linked cholinergic M1 receptor, both of which have been found to be enriched on cortical pyramidal neurones2. Concepts arising from this work on cultured cells 1,3 and animals modelling an aspect of Alzheimer's disease (selective cortical pyramidal neurone loss2) have recently been extended to humans. Here, negative regulation of phospholipase-C activity was found to be associated with lower concentrations of secreted non-amyloidogenic APP. This was based on ventricular cerebrospinal fluid samples obtained during air encephalography from patients receiving lithium salts and drugs with anti-cholinergic

1 Ridley,R. M. and Baker, H. F. (1993) Trends Neurosci. 16, 425-426 2 Dickinson, A. G., Bruce, M. E., Outram, G. W. and Kimberlin, R. H. (1984) in Proceedings of Workshop on

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(Tateishi, J., ed.), pp. 105-118, Japanese Ministry of Health and Welfare Dickinson,A. G. and Fraser,H. (1979) in Slow Transmissible Diseases of the Nervous System, Vol. 1 (Prusiner,S. B. and Hadlow, W. J., eds), pp. 367-385, Academic Press De Armond, S. J. et aL (1993) Proc. Natl Acad. ScL USA 90, 6449-6453 Kimberlin, R. H., Walker, C. A. and Fraser, H. (1989)J. Gen. Virol. 70, 2017-2025 Kascsak, R. J., Rubenstein, R. and Carp, R. I. (1991) in Current Topics in Microbiology

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Immunology

(Chesebro, B. W., ed.), pp. 139-152, Springer-Verlag 7 Carp, R. I. and Rubenstein,R. (1991) in Seminars in Virology (Haase,A. T., ed.), pp. 203-213, Academic Press 8 Carp, R. I., Kim, Y. S. and Callahan, S. M. (1990) J. Infect. Dis. 161, 462-466 9 Prusiner, S. B. et aL (1983) Cell 35, 349-358 10 Gabizon, R., McKinley, M. P. and Prusiner,S. B. (1987) Proc. Natl Acad. Sci. USA 84, 4017-4021 11 Bellinger-Kawahara,C. G., Kempner, E., Growth, D., Gabizon, R. and Prusiner, S. B. (1988) Virology 164, 533-541 12 Prusiner, S. B. (1991) Science 252, 1515-1522 13 Hsiao,K. K. etal. (1990) Science 250, 1587- 1590 14 Carp, R. I. and Callahan,S. M. (1991) J. Gen. Virol. 72, 293-298 15 Carp, R. I. et aL (1989) Alzhetmer's Dis. Assoc. Disord. 3, 79-99

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disease is the loss of cholinergic modulation. Second, a study of postmortem brain tissue, collected so as to minimize autolysis, revealed an inverse relationship between cortical pyramidal neurone number and APP in the supernatant fraction of cerebral cortex 4. It remains to be established what effect the degree of neuronal deactivation (glutamatergic hypoactivity and cholinergic dysfunction) has on the novel nonamyloidogenic homologue of APP (APLP2 or APPH), considered to be the major Kunitz protease inhibitor-containing molecule of human brain cell membranes 5. Likewise, it is important to discover any effect of transmitter replacement therapy on an understudied aberrant mechanism - signal-transduction-dependent phosphorylation 6 and dephosphorylation of tau protein 7. This should include investigation of any interaction between this mechanism and apolipoprotein E3 (Ref. 8). Strittmatter and Roses (pers. commun.) find that E3 binds

to the microtubule-binding repeat designed to improve the state of of tau, and suggest that E3 might pyramidal neurone activation. inhibit tau self-assembly into paired helical filaments (PHF) by mechDavid M. Bowen anisms independent of phosPaul T. Francis phorylation. However, diminished lain P. Chessell or lack of E4 binding to tau and Marie- Therese Webster phosphorylated-tau compared to Institute of Neurology, Miriam Marks Dept of E3, suggest a specific, testable Neurochemistry, 1 Wakefield Street, London, hypothesis that E3 plays a protec- UK WCIN 1PJ. tive role in PHF and neurofibrillary tangle formation. The binding of E3 (or E2) to tau might protect References tau from phosphorylation (W. J. 1 Webster, M-T., Vekrellis, K., Francis, P. T., Pearce,B. R. and Bowen, D. M. Strittmatter and A. D. Roses, pers. (1993) Biochem. Soc. Trans. 21,239S commun.) and this might be influ2 Chessell, I. P., Francis,P. T., Pangalos, M. N., Pearson,R. C. A. and Bowen, enced by the degree of neuronal D. M. (1993) Brain Res. 632, 86-94 activation. Hyperphosphorylation 3 Selkoe, D. J. (1993) Trends Neurosci. of tau is considered to be fol16, 403-409 lowed by cortical pyramidal neur4 Clarke, N. A. eta/. (1993) Neuroone degeneration (for example, degeneration 2,243-248 5 Webster, M-T. et al. Brain Res. (in tangle pathology), glutamatergic press) hypoactivity and cognitive 6 Mandelkow, E. M. et aL (1993) Ann. decline 9. N.Y. Acad. Sci. 695, 209-216 The recent developments in 7 Robertson,J. etal. (1993) Dementia 4, 256-263 this rapidly changing field suggest 8 Saunders, A. M. et a/. (1993) that it is now not inconceivable Neurology 43, 1467-1472 that there will be a neurotrans9 Francis, P. T., Sims, N. R., Procter, mitter-based treatment for AIzA. W. and Bowen, D. M. (1993) helmet's disease using a drug J. Neurochem. 60, 1589-1604

Neuroscience Trends Some recent Trends articles of interest to neuroscientists: Molecular biology of prion diseases by Charles Weissmann Trends in Cell Biology 4, 10-14

Targeting of mRNAs to domains of the endoplasmic reticulum by Thomas W. Okita, Xingxiang Li and Mark W. Roberts Trends in Cell Biology 4, 91-96 Antisense oligonudeotide strategies in neuropharmacology by C. Wahlestedt Trends in Pharmacological Sciences 15, 42-46 Protein kinase C: is its pivotal role in cellular activation overstated? by S. E. Wilkinson and T. J. Hallam Trends in Pharmacological Sciences 15, 53-57 Gene transfer and antisense nucleic acid techniques by N. Miller and R. G. Vile Parasitology Today 10, 92-97 Genes for normal and diseased mental states by Frank Ashall Trends m Genetics 10, 37-39 The 3Rs of life: Ras, Raf and growth regulation by ShonaA. Moodie and Alan Wolfman Trends in Genetics 10, 44-48 Role of the #-amyloid precursor protein in Alzheimer's disease by Frank Ashall and Alison M. Goate Trends in Biochemical Sciences 19, 42-46

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