Memory impairment progressing to dementia is the main clinical symptom of Alzheimer's disease (AD). AD is characterized histologically by the presence of beta-amyloid (Abeta) plaques and neurofibrillary tangles in specific brain regions. Although Abeta derived from the Abeta precursor protein (beta-APP) is believed to play a central etiological role in AD, it is not clear whether soluble and/or fibrillar forms are responsible for the memory deficit. We have generated and previously described mice expressing human wild-type beta-APP(751) isoform in neurons. These transgenic mice recapitulate early histopathological features of AD and form Abeta deposits but no plaques. Here we describe a specific and progressive learning and memory impairment in these animals. In the Morris water maze, a spatial memory task sensitive to hippocampal damage, one pedigree already showed significant differences in acquisition in 3-month-old mice that increased in severity with age and were expressed clearly in 6-month- and 2-year-old animals. The second transgenic pedigree displayed a milder impairment with a later age of onset. Performance deficits significantly decreased during the 6 days of training in young but not in aged transgenic animals. Both pedigrees of the transgenic mice differed from wild-type mice by less expressed increase of escape latencies after the platform position had been changed in the reversal experiment and by failure to prefer the goal quadrant in probe trials. Both pedigrees performed at wild-type level in a number of other tests (open field exploration and passive and active place avoidance). The results suggest that plaque formation is not a necessary condition for the neuronal beta-APP(751) transgene-induced memory impairment, which may be caused by beta-APP overexpression, isoform misexpression, or elevated soluble Abeta.

Institute of Physiology Academy of Sciences of the Czech Republic Videnska 1083 142 20 Prague 4 Krc Czech Republic

Zobrazit více v PubMed

Selkoe D. Nature (London) 1999;399,Suppl.:23–31. PubMed

Lendon C L, Ashall F, Goate A M. J Am Med Assoc. 1997;277:825–831. PubMed

Mattson M P, Cheng B, Culwell A R, Esch F S, Lieberburg I, Rydell R E. Neuron. 1993;10:243–254. PubMed

Milward E A, Papadopoulos R, Fuller S J, Moir R D, Small D, Beyreuther K, Masters C. Neuron. 1992;9:129–137. PubMed

Saitoh T, Sundsmo M, Roch J M, Kimura N, Cole G, Schubert D, Oltersdorf T, Schenk D B. Cell. 1989;58:615–622. PubMed

Smith-Swintosky V L, Pettigrew L C, Craddock S D, Culwell A R, Rydell R E, Mattson M P. J Neurochem. 1994;63:781–784. PubMed

Takahashi M, Doré S, Ferris C D, Tomita T, Sawa A, Wolosker H, Borchelt D, Iwatsubo T, Kim S-H, Snyder S. Neuron. 2000;28:461–473. PubMed

Pike C J, Burkick D, Walencewicz A J, Glabe C G, Cotman C W. J Neurosci. 1993;13:1676–1687. PubMed PMC

McKee A C, Kowall N W, Schumacher J S, Beal M F. Amyloid Int J Exp Clin Invest. 1998;5:1–9. PubMed

Emere M, Geula C, Ransil B J, Mesulam M-M. Neurobiol Aging. 1992;13:553–339. PubMed

Lorenzo A, Yankner B A. Proc Natl Acad Sci USA. 1994;91:12243–12247. PubMed PMC

Hartley D M, Walsh D M, Ye C P, Diehl T, Vasquez S, Vassilev P M, Teplow D B, Selkoe D J. J Neurosci. 1999;19:8876–8884. PubMed PMC

Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G. Science. 1996;274:99–102. PubMed

Giulian D, Haverkamp L J, Li J, Karshin W L, Yu J, Tom D, Li X, Kirkpatrick J B. Neurochem Int. 1995;27:119–137. PubMed

Campbell A. Med Hypotheses. 2001;56:388–391. PubMed

Dodart J-C, Meziane H, Mathis C, Ungerer A, Bales K R, Paul S M. Behav Neurosci. 1999;111:982–990. PubMed

Janus C, Pearson J, McLaurin J, Mathews P M, Jiang Y, Schmidt S D, Chishti M A, Horne P, Heslin D, Westaway D. Nature (London) 2000;408:979–982. PubMed

Morgan D, Diamond D M, Gottschall P E, Ugen K E, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Arendash G W. Nature (London) 2000;408:982–985. PubMed

Duff K. Curr Opin Biotechnol. 1998;9:561–564. PubMed

Price D L, Tanzi R E, Borchelt D R, Sisodia S S. Annu Rev Genet. 1998;32:461–493. PubMed

Higgins L S. Mol Med Today. 1999;5:274–276. PubMed

Janus C, Chishti M A, Westaway D. Biochim Biophys Acta. 2000;1502:63–75. PubMed

Quon D, Wang Y, Marian Scardina J, Murakami K, Cordell B. Nature (London) 1991;352:239–241. PubMed

Higgins L S, Holtzman D M, Rabin J, Mobley W C, Cordell B. Ann Neurol. 1994;35:598–607. PubMed

Higgins L S, Rodems J M, Catalano R, Quon D, Cordell B. Proc Natl Acad Sci USA. 1995;92:4402–4403. PubMed PMC

Neve R L, Finch E A, Dawes L R. Neuron. 1988;1:669–677. PubMed

Motte J, Williams R S. Acta Neuropathol. 1989;77:535–546. PubMed

Burger P C, Vogel F S. Am J Pathol. 1973;73:457–476. PubMed PMC

Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Zhao J. Nature (London) 1995;373:523–527. PubMed

Irizarry M C, Soriano F, McNamara M, Page K J, Schenk D, Games D, Hyman B T. J Neurosci. 1997;17:7053–7059. PubMed PMC

Hsiao K. Prog Brain Res. 1998;117:335–341. PubMed

Holcomb L, Gordon M N, McGowan E, Yu X, Benkovic S, Jantzen P, Wright K, Saad I, Mueller R, Duff K. Nat Med. 1998;4:97–100. PubMed

Chen G, Chen K S, Knox J, Inglis J, Bernard A, Martin S J, Justice A, McConlogue L, Games D, Morris R G. Nature (London) 2000;408:975–979. PubMed

Moran P M, Higgins L S, Cordell B, Moser P C. Proc Natl Acad Sci USA. 1995;93:5341–5345. PubMed PMC

Morris R J. J Neurosci Methods. 1984;11:47–60. PubMed

Kaminsky Y, Krekule I. Physiol Res. 1997;46:223–231. PubMed

Cimadevilla J M, Fenton A A, Bures J. Brain Res Bull. 2001;54:559–563. PubMed

Liu Q, Kawai H, Berg D. Proc Natl Acad Sci USA. 2001;98:4734–4739. PubMed PMC

Gray R, Rajan A S, Radcliffe K A, Yakehiro M, Dani J A. Nature (London) 1996;383:713–716. PubMed

Zhang Z W, Coggan J S, Berg D K. Neuron. 1996;17:1231–1240. PubMed

Levin E D, Bettegowda C, Blosser J, Gordon J. Behav Pharmacol. 1999;10:675–880. PubMed

Meyer E M, Tay E T, Papke R L, Meyers C, Huang G L, de Fiebre C M. Brain Res. 1997;768:49–56. PubMed

Alkadhi K A, Al-Hijailan R S, Malik K, Hogan Y H. J Neurosci. 2001;21:3515–3520. PubMed PMC

Shibuki K, Kimura S, Wakatsuki H. Eur J Neurosci. 2001;13:609–616. PubMed

Zhuo M, Laitinen J T, Li X C, Hawkins R D. Learn Mem. 1998;5:467–480. PubMed PMC

Higgins G A, Oyler G A, Neve R L, Chen K S, Gage F H. Proc Natl Acad Sci USA. 1990;87:3032–3036. PubMed PMC

Fiore M, Angelucci F, Alleva E, Branchi I, Probert L, Aloe L. Behav Brain Res. 2000;112:165–175. PubMed

Gold L H, Heyser C J, Roberts A J, Henriksen S J, Steffensen S C, Siggins G R, Bellinger F P, Chiang C S, Powell H C, Campbell I L. Adv Exp Med Biol. 1996;402:199–205. PubMed

Arendash G W, King D L, Gordon M N, Morgan D, Hatcher J M, Hope C E, Diamond D M. Brain Res. 2001;891:42–53. PubMed

Chapman P F, White G L, Jones M W, Cooper-Blacketer D, Marshall V J, Irizarry M, Younkin L, Good M A, Bliss T V, Hsiao K K. Nat Neurosci. 1999;2:271–276. PubMed

Holcomb L A, Gordon M N, Jantzen P, Hsiao K, Duff K, Morgan D. Behav Genet. 1999;29:177–185. PubMed

King D L, Arendash G W, Crawford F, Sterk T, Menendez J, Mullan M J. Behav Brain Res. 1999;103:145–162. PubMed

Janus C, D'Amelio S, Amitay O, Chishti M A, Strome R, Fraser P, Carlson G A, Roder J C, St. George-Hyslop P, Westaway D. Neurobiol Aging. 2000;21:541–549. PubMed

Cimadevilla J M, Fenton A A, Bures J. Neurosci Lett. 2000;285:53–56. PubMed