Showing papers by "Michael T. Lin published in 2004"

Oligomerization of Alzheimer's β-Amyloid within Processes and Synapses of Cultured Neurons and Brain

Abstract: Multiple lines of evidence implicate β-amyloid (Aβ) in the pathogenesis of Alzheimer's disease (AD), but the mechanisms whereby Aβ is involved remain unclear. Addition of Aβ to the extracellular space can be neurotoxic. Intraneuronal Aβ42 accumulation is also associated with neurodegeneration. We reported previously that in Tg2576 amyloid precursor protein mutant transgenic mice, brain Aβ42 localized by immunoelectron microscopy to, and accumulated with aging in, the outer membranes of multivesicular bodies, especially in neuronal processes and synaptic compartments. We now demonstrate that primary neurons from Tg2576 mice recapitulate the in vivo localization and accumulation of Aβ42 with time in culture. Furthermore, we demonstrate that Aβ42 aggregates into oligomers within endosomal vesicles and along microtubules of neuronal processes, both in Tg2576 neurons with time in culture and in Tg2576 and human AD brain. These Aβ42 oligomer accumulations are associated with pathological alterations within processes and synaptic compartments in Tg2576 mouse and human AD brains.

Increased plaque burden in brains of APP mutant MnSOD heterozygous knockout mice

Abstract: A growing body of evidence suggests a relationship between oxidative stress and β-amyloid (Aβ) peptide accumulation, a hall-mark in the pathogenesis of Alzheimer's disease (AD). However, a direct causal relationship between oxidative stress and Aβ pathology has not been established in vivo. Therefore, we crossed mice with a knockout of one allele of manganese superoxide dismutase (MnSOD), a critical antioxidant enzyme, with Tg19959 mice, which overexpress a doubly mutated human β-amyloid precursor protein (APP). Partial deficiency of MnSOD, which is well established to cause elevated oxidative stress, significantly increased brain Aβ levels and Aβ plaque burden in Tg19959 mice. These results indicate that oxidative stress can promote the pathogenesis of AD and further support the feasibility of antioxidant approaches for AD therapy. (Less)

COMMUNICATION Increased plaque burden in brains of APP mutant MnSOD heterozygous knockout mice

Abstract: A growing body of evidence suggests a relationship between oxidative stress and b-amyloid (Ab) peptide accumulation, a hallmark in the pathogenesis of Alzheimer’s disease (AD). However, a direct causal relationship between oxidative stress and Ab pathology has not been established in vivo. Therefore, we crossed mice with a knockout of one allele of manganese superoxide dismutase (MnSOD), a critical antioxidant enzyme, with Tg19959 mice, which overexpress a doubly mutated human b-amyloid precursor protein (APP). Partial deficiency of MnSOD, which is well established to cause elevated oxidative stress, significantly increased brain Ab levels and Ab plaque burden in Tg19959 mice. These results indicate that oxidative stress can promote the pathogenesis of AD and further support the feasibility of anti

Heterologous mitochondrial DNA recombination in human cells

Abstract: Inter-molecular heterologous mitochondrial DNA (mtDNA) recombination is known to occur in yeast and plants. Nevertheless, its occurrence in human cells is still controversial. To address this issue we have fused two human cytoplasmic hybrid cell lines, each containing a distinct pathogenic mtDNA mutation and specific sets of genetic markers. In this hybrid model, we found direct evidence of recombination between these two mtDNA haplotypes. Recombinant mtDNA molecules in the hybrid cells were identified using three independent experimental approaches. First, recombinant molecules containing genetic markers from both parental alleles were demonstrated with restriction fragment length polymorphism of polymerase chain reaction products, by measuring the relative frequencies of each marker. Second, fragments of recombinant mtDNA were cloned and sequenced to identify the regions involved in the recombination events. Finally, recombinant molecules were demonstrated directly by Southern blot using appropriate combinations of polymorphic restriction sites and probes. This combined approach confirmed the existence of heterogeneous species of recombinant mtDNA molecules in the hybrid cells. These findings have important implications for mtDNA-related diseases, the interpretation of human evolution and population genetics and forensic analyses based on mtDNA genotyping.

Diffusion tensor imaging in the diagnosis of primary lateral sclerosis.

Abstract: Purpose To evaluate the utility of MR diffusion tensor imaging in diagnosing primary lateral sclerosis (PLS) Materials and Methods Five patients who met clinical criteria for a diagnosis of PLS, and two patients with possible PLS of less than three years duration and eight normal volunteers were studied using MR diffusion tensor imaging Results All seven patients showed decreased diffusion anisotropy and increased diffusion constant in the PLIC, with complete separation from a normal control group, including patients early in the course of the illness Conclusion Quantitative diffusion tensor imaging appears to be a useful test to detect upper motor neuron damage and hence to help to establish the diagnosis of PLS J Magn Reson Imaging 2004;19:34–39 © 2003 Wiley-Liss, Inc