Overexpression of heat shock proteins in pallido-nigral axonal spheroids of nonhuman aged primates

Fukuda, Takahiro; Shimizu, Jun; Furuhata, Hiroshi; Abe, Toshiaki; Shimizu, Keiko; Oishi, Takao; Ogihara, Makoto; Kubota, Jun; Sasaki, Akira; Sasaki, Kohsuke; Azuma, Takashi; Umemura, Shin‐ichiro

doi:10.1007/s00401-005-1030-8

Cited by 10 publications

(8 citation statements)

References 39 publications

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“…Preparation of brain sections and immunostaining were performed according to a procedure previously described 21,26 . Sliced sections were incubated with the primary antibodies and visualized by Alexa 555-conjugated anti-rabbit IgG, Alexa 488-conjugated streptavidin (Invitrogen, This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Hematopoietic Stem Cell Gene Therapy Corrects Neuropathic Phenotype in Murine Model of Mucopolysaccharidosis Type II

et al. 2015

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Mucopolysaccharidosis type II (MPS II) is a neuropathic lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS), which leads to the accumulation of glycosaminoglycans (GAGs). We demonstrated that biochemical alterations in the brains of MPS II mice are not corrected by bone marrow transplantation (BMT) or enzyme replacement therapy, although BMT has been shown to be effective for other neurodegenerative MPSs, such as Hurler syndrome. In this study, we demonstrated that lentiviral isogeneic hematopoietic stem cell (HSC) gene therapy corrected neuronal manifestations by ameliorating lysosomal storage and autophagic dysfunction in the brains of MPS II mice. IDS-transduced HSCs increased enzyme activity both in various visceral organs and the CNS. Decreased levels of GAGs were observed in many organs, including cerebra, after transplantation of IDS-transduced HSCs. In addition, lentiviral HSC gene therapy normalized the secondary accumulation of autophagic substrates, such as p62 and ubiquitin-protein conjugates, in cerebra. Furthermore, in contrast to naive MPS II mice, there was no deterioration of neuronal function observed in transplant recipients. These results indicated that lentiviral HSC gene therapy is a promising approach for the treatment of CNS lesions in MPS II.

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Section: Immunohistochemistrymentioning

confidence: 99%

Hematopoietic Stem Cell Gene Therapy Corrects Neuropathic Phenotype in Murine Model of Mucopolysaccharidosis Type II

et al. 2015

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“…One report indicated that no difference in MAP-2 and SYN was observed between young adult (5-year) and old (18-year) nonhuman primates; however, there were only two old animals in the study and the analysis was performed in the pallidonigral region (Fukuda et al 2005). However, since rhesus macaques in captivity can live longer than 30 years (Uno et al 1996), the current study includes much older animals and examined cortical regions linked to cognitive function.…”

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confidence: 95%

Age-related decreases in SYN levels associated with increases in MAP-2, apoE, and GFAP levels in the rhesus macaque prefrontal cortex and hippocampus

Haley

Kohama

Urbanski

et al. 2010

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Loss of synaptic integrity in the hippocampus and prefrontal cortex (PFC) may play an integral role in age-related cognitive decline. Previously, we showed age-related increases in the dendritic marker microtubule associated protein 2 (MAP-2) and the synaptic marker synaptophysin (SYN) in mice. Similarly, apolipoprotein E (apoE), involved in lipid transport and metabolism, and glial fibrillary acidic protein (GFAP), a glia specific marker, increase with age in rodents. In this study, we assessed whether these four proteins show similar age-related changes in a nonhuman primate, the rhesus macaque. Freefloating sections from the PFC and hippocampus from adult, middle-aged, and aged rhesus macaques were immunohistochemically labeled for MAP-2, SYN, apoE, and GFAP. Protein levels were measured as area occupied by fluorescence using confocal microscopy as well as by Western blot. In the PFC and hippocampus of adult and middle-aged animals, the levels of SYN, apoE, and GFAP immunoreactivity were comparable but there was a trend towards higher MAP-2 levels in middle-aged than adult animals. There was significantly less SYN and more MAP-2, apoE, and GFAP immunoreactivity in the PFC and hippocampus of aged animals compared to adult or middle-aged animals. Thus, the age-related changes in MAP-2, apoE, and GFAP levels were similar to those previously observed in rodents. On the other hand, the age-related changes in SYN levels were not, but were similar to those previously observed in the aging human brain. Taken together, these data emphasize the value of the rhesus macaque as a pragmatic translational model for human brain aging.

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“…Large quantities of lipofuscin deposits in all animals and large granules across an extensive area were observed. Axonal spheroids that were identified as “Pallido-nigral axonal spheroids” (Fukuda et al 2005) were observed in the globus pallidus of the basal ganglia in all animals. These findings were significantly increased in middle-aged monkeys when compared with young monkeys.…”

Section: Discussionmentioning

confidence: 99%

Age-Related Lesions in the Cerebrum in Middle-Aged Female Cynomolgus Monkeys

et al. 2010

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Alzheimer's disease (AD) in humans is a progressive neurogenic disease that can be linked with such characteristic pathological findings in the cerebrum as senile plaques (SPs), neurofibrillary tangles (NFTs), cerebral amyloid angiopathy (CAA), and neuronal loss. In the present study, the authors investigated the age-related morphological changes in 12 middle-aged and 12 young cynomolgus monkeys. Low numbers of neurons and astrocytes in the hippocampal region in cynomolgus monkeys accompanied ageing, and there was a high number of microglial cells; however, no clearly neurotoxic abnormalities due to beta-amyloid were noted before the age of 20 years. The onset of SPs and CAA in the cerebrum in cynomolgus monkeys can occur before the age of 20 years. SPs were almost all categorized as diffuse plaques (DPs); they did not have amyloid cores and were unaccompanied by neuritic degeneration. In cynomolgus monkeys, SPs (DPs) occur before the appearance of CAA. From the above, it was concluded that cynomolgus monkeys showed pathological changes due to ageing similar to those related to Alzheimer's disease in humans, even before they were 20 years old.

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Overexpression of heat shock proteins in pallido-nigral axonal spheroids of nonhuman aged primates

Cited by 10 publications

References 39 publications

Hematopoietic Stem Cell Gene Therapy Corrects Neuropathic Phenotype in Murine Model of Mucopolysaccharidosis Type II

Hematopoietic Stem Cell Gene Therapy Corrects Neuropathic Phenotype in Murine Model of Mucopolysaccharidosis Type II

Age-related decreases in SYN levels associated with increases in MAP-2, apoE, and GFAP levels in the rhesus macaque prefrontal cortex and hippocampus

Age-Related Lesions in the Cerebrum in Middle-Aged Female Cynomolgus Monkeys

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