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The Journal of Neuroscience, November 2, 2005, 25(44):10220-10229; doi:10.1523/JNEUROSCI.2773-05.2005

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Neurobiology of Disease
Nigrostriatal Dysfunction in Familial Alzheimer's Disease-Linked APPswe/PS1E9 Transgenic Mice

Sylvia E. Perez,¹ Orly Lazarov,² James B. Koprich,¹ Er-Yun Chen,¹ Virginia Rodriguez-Menendez,³ Jack W. Lipton,¹ Sangram S. Sisodia,² and Elliott J. Mufson¹

¹Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612, ²Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois 60637, and ³Department of Neuroscience and Biomedical Technologies, University of Milano-Bicocca, 20052 Monza (MI), Italy

Alzheimer's disease (AD) is often accompanied by extrapyramidal signs attributed to nigrostriatal dysfunction. The association between amyloid deposition and nigrostriatal degeneration is essentially unknown. We showed previously that the striatum and the substantia nigra of transgenic mice harboring familial AD (FAD)-linked APPswe/PS1E9 mutants exhibit morphological alterations accompanied by amyloid- (A) deposition (Perez et al., 2004). In the present study, we further investigated the interaction between A deposition and dopaminergic nigrostriatal dysfunction, by correlating morphological and biochemical changes in the nigrostriatal pathway with amyloid deposition pathology in the brains of 3- to 17-month-old APPswe/PS1E9 transgenic mice and age-matched wild-type controls. We show that A deposition is pronounced in the striatum of APPswe/PS1E9 mice at 6 months of age, and the extent of deposition increases in an age-dependent manner. Tyrosine hydroxylase (TH)-positive dystrophic neurites with rosette or grape-like cluster disposition are observed adjacent to A plaques and display multilaminar, multivesicular, and dense-core bodies as well as mitochondria. In addition, an age-dependent increase of TH protein levels are shown in nigral cells in these mutant mice. Using HPLC analysis, we found a reduction in the dopamine metabolite DOPAC in the striatum of these mice. These findings show a close association between amyloid deposition and nigrostriatal pathology and suggest that altered FAD-linked amyloid metabolism impairs, at least in part, the function of dopaminergic neurons.

Key words: Alzheimer's disease; amyloid; nigrostriatal; transgenics; dopamine; parkinsonism

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Received July 5, 2005; revised September 23, 2005; accepted September 27, 2005.

This article has been cited by other articles:

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