Nigrostriatal dysfunction in familial Alzheimer's disease-linked APPswe/PS1ΔE9 transgenic mice
Document Type
Article
Abstract
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/PS1ΔE9 mutants exhibit morphological alterations accompanied by amyloid-β (Aβ) deposition (Perez et al., 2004). In the present study, we further investigated the interaction between Aβ 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/PS1ΔE9 transgenic mice and age-matched wild-type controls. We show that Aβ deposition is pronounced in the striatum of APPswe/PS1ΔE9 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 Aβ 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. Copyright © 2005 Society for Neuroscience.
Keywords
Alzheimer's disease, Amyloid, Dopamine, Nigrostriatal, Parkinsonism, Transgenics
Publication Date
11-2-2005
Publication Title
Journal of Neuroscience
ISSN
02706474
E-ISSN
02706474
Volume
25
Issue
44
First Page
10220
Last Page
10229
PubMed ID
16267229
Digital Object Identifier (DOI)
10.1523/JNEUROSCI.2773-05.2005
Recommended Citation
Perez, Sylvia E.; Lazarov, Orly; Koprich, James B.; Chen, Er Yun; Rodriguez-Menendez, Virginia; Lipton, Jack W.; Sisodia, Sangram S.; and Mufson, Elliott J., "Nigrostriatal dysfunction in familial Alzheimer's disease-linked APPswe/PS1ΔE9 transgenic mice" (2005). Translational Neuroscience. 1637.
https://scholar.barrowneuro.org/neurobiology/1637