Enhanced expression of the voltage-dependent anion channel 1 (VDAC1) in Alzheimer's disease transgenic mice: an insight into the pathogenic effects of amyloid-ß.

The mitochondrial voltage-dependent anion channel 1 (VDAC1) is involved in the release of apoptotic proteins with possible relevance in Alzheimer's disease (AD) neuropathology. Through proteomic analysis followed by Western blotting and immunohistochemical techniques, we have found that VDAC1 is overexpressed in the hippocampus from amyloidogenic AD transgenic mice models. VDAC1 was also overexpressed in postmortem brain tissue from AD patients at an advanced stage of the disease. Interestingly, amyloid-ß (Aß) soluble oligomers were able to induce upregulation of VDAC1 in a human neuroblastoma cell line, further supporting a correlation between Aß levels and VDAC1 expression. In hippocampal extracts from transgenic mice, a significant increase was observed in the levels of VDAC1 phosphorylated at an epitope that is susceptible to phosphorylation by glycogen synthase kinase-3ß, whose activity was also increased. The levels of hexokinase I (HXKI), which interacts with VDAC1 and affects its function, were decreased in mitochondrial samples from AD models. Since phospho-VDAC and reduced HXKI levels favors a VDAC1 conformational state more prone to the release proapoptotic factors, regulation of the function of this channel may be a promising therapeutic approach to combat AD.

Increased sensitivity to MPTP in human alpha-synuclein A30P transgenic mice.

In addition to genetic factors, environmental factors have long been suspected to contribute to the pathogenesis of Parkinson's disease (PD). We investigated the possible interaction between genetic factors and neurotoxins by testing whether alpha-synuclein A30P Tg5093 transgenic mice show increased sensitivity to secondary toxic insults like 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or rotenone. While sensitivity to chronic treatment with rotenone was not enhanced in the Tg5093 line, chronic treatment with 80 or 150 mg/kg MPTP resulted in increased deterioration of the nigrostriatal dopaminergic system as assessed by quantitation of nigral tyrosine hydroxylase (TH) positive neurons and striatal dopamine (DA) levels in Tg5093 mice when compared to non-transgenic littermate controls. Thus, the results of this study demonstrate a role for the overexpression of mutant human alpha-synuclein A30P in increased vulnerability of DA neurons to MPTP.

Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice.

Even though the idea that amyloid beta peptide accumulation is the primary event in the pathogenesis of Alzheimer's disease has become the leading hypothesis, the causal link between aberrant amyloid precursor protein processing and tau alterations in this type of dementia remains controversial. We further investigated the role of beta-amyloid production/deposition in tau pathology and neuronal cell death in the mouse brain by crossing Tg2576 and VLW lines expressing human mutant amyloid precursor protein and human mutant tau, respectively. The resulting double transgenic mice showed enhanced amyloid deposition accompanied by neurofibrillary degeneration and overt neuronal loss in selectively vulnerable brain limbic areas. These findings challenge the idea that tau pathology in Alzheimer's disease is merely a downstream effect of amyloid production/deposition and suggest that reciprocal interactions between beta-amyloid and tau alterations may take place in vivo.