Nigrostriatal Dysfunction in Familial Alzheimer's Disease-Linked APPswe/PS1ΔE9 Transgenic Mice

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/PS1⌬E9 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/PS1⌬E9 transgenic mice and age-matched wild-type controls. We show that A␤ deposition is pronounced in the striatum of APPswe/PS1⌬E9 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.

Neuroimaging of individuals with Down’s syndrome at-risk for dementia: Evidence for possible compensatory events

“…The observation of DMR correlating to increased GMR and to decreased GM in the caudate and lentiform nucleus may be consistent with evidence suggesting a role of the dopaminergic system in AD (Perez, Lazarov et al 2005) and with a possible dysfunction or disconnection between parts of the basal ganglia and the frontal lobe in DS (Haier, Hazen et al 1998). Our thalamus finding may be part of this network, but these areas are not often reported in similar studies of dementia.…”

Galanin – 25 years with a multitalented neuropeptide

“…2A -C). Since neuron loss was not evident at this age [63,64], these observations suggest that GAL is triggered by amyloidosis-related neurotoxicity rather than frank neurodegeneration in transgenic animal models of AD. Whether amyloid plaque deposition, which is prominent in vulnerable cognitive brain regions in AD [65,66], also triggers GAL overexpression in these areas in the human condition remains an open question.…”

Amyloid Deposition Begins in the Striatum of Presenilin-1 Mutation Carriers from Two Unrelated Pedigrees

“…It may be that the cellular milieu of the striatum is particularly prone to amyloid deposition under these conditions of overproduction. Although the relevance to human AD is not known, it should be noted that striatal amyloid deposition has been described in a PS1/APP double-transgenic mouse model (Perez et al, 2005). The AP3(45) and AP5(49) subjects, who carry a clinical diagnosis of AD, both had lower PiB retention in frontal, temporoparietal, and precuneus cortices than most very mildly impaired sporadic AD subjects.…”