Accumulation of Intracellular Amyloid-β Peptide (Aβ 1–40) in Mucopolysaccharidosis Brains

Ginsberg, Stephen D.; Galvin, James E.; Lee, Virginia M.‐Y.; Rorke, Lucy B.; Dickson, Dennis W.; Wolfe, John H.; Jones, M. Z.; Trojanowski, John Q.

doi:10.1097/00005072-199908000-00004

Cited by 59 publications

(37 citation statements)

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“…Others have looked for but did not find hyperphosphorylated tau in brain of human MPS patients or animal models (26,27). From our experience with the MPS III B mouse model, we believe that hyperphosphorylated tau can be easily missed.…”

Section: Discussionmentioning

confidence: 78%

Sanfilippo syndrome type B, a lysosomal storage disease, is also a tauopathy

Ohmi¹,

Kudo

Ryazantsev

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

124

100

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Sanfilippo syndrome type B (mucopolysaccharidosis III B, MPS III B)is an autosomal recessive, neurodegenerative disease of children, characterized by profound mental retardation and dementia. The primary cause is mutation in the NAGLU gene, resulting in deficiency of ␣-N-acetylglucosaminidase and lysosomal accumulation of heparan sulfate. In the mouse model of MPS III B, neurons and microglia display the characteristic vacuolation of lysosomal storage of undegraded substrate, but neurons in the medial entorhinal cortex (MEC) display accumulation of several additional substances. We used whole genome microarray analysis to examine differential gene expression in MEC neurons isolated by laser capture microdissection from Naglu ؊/؊ and Naglu ؉/؊ mice. Neurons from the lateral entorhinal cortex (LEC) were used as tissue controls. The highest increase in gene expression (6-to 7-fold between mutant and control) in MEC and LEC neurons was that of Lyzs, which encodes lysozyme, but accumulation of lysozyme protein was seen in MEC neurons only. Because of a report that lysozyme induced the formation of hyperphosphorylated tau (Ptau) in cultured neurons, we searched for P-tau by immunohistochemistry. P-tau was found in MEC of Naglu ؊/؊ mice, in the same neurons as lysozyme. In older mutant mice, it was also seen in the dentate gyrus, an area important for memory. Electron microscopy of dentate gyrus neurons showed cytoplasmic inclusions of paired helical filaments, P-tau aggregates characteristic of tauopathies-a group of age-related dementias that include Alzheimer disease. Our findings indicate that the Sanfilippo syndrome type B should also be considered a tauopathy.hyperphosphorylated tau ͉ lysozyme ͉ mucopolysaccharidosis ͉ entorhinal cortex ͉ gene expression microarray

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Section: Discussionmentioning

confidence: 78%

Sanfilippo syndrome type B, a lysosomal storage disease, is also a tauopathy

Ohmi¹,

Kudo

Ryazantsev

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

124

100

View full text Add to dashboard Cite

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“…1,3 While detailed mechanisms of pathology, especially the neuropathology of MPS III, are not yet well understood, numerous studies have reported cascades of complex secondary pathological events in the CNS, including broad metabolic impairments, [4][5][6] neuroinflammation, 5,7-11 oxidative stress, 10,12 autophagy, 13,14 and neurodegeneration. 7,9,11,[15][16][17][18][19][20] It is worth noting that many of these secondary neuropathological features of MPS IIIB, such as b-amyloid (Ab) aggregation, 15,18 tauopathy, 17,18 synucleinopathy, 16,19 oxidative stress, 10,12 and neuroimflammation, 5,[7][8][9][10][11] are also common hallmarks of other neurodegenerative diseases like Alzheimer's (AD) 21,22 and Parkinson's disease (PD). 23,24 In addition, our recent studies demonstrate widespread profound neuropathology in the peripheral nervous system (PNS), 25 indicating that neuropathological manifestation affects the entire nervous system.…”

Section: Mucopolysaccharidosis (Mps) Iiib (Online Mendelian Inheritanmentioning

confidence: 99%

Near-Complete Correction of Profound Metabolomic Impairments Corresponding to Functional Benefit in MPS IIIB Mice after IV rAAV9-hNAGLU Gene Delivery

Meadows

Ware

et al. 2017

Molecular Therapy

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Mucopolysaccharidosis (MPS) IIIB is a lysosomal storage disease with complex CNS and somatic pathology due to a deficiency in a-N-acetylglucosaminidase (NAGLU). Using global metabolic profiling by mass spectrometry targeting 361 metabolites, this study detected significant decreases in 225 and increases in six metabolites in serum samples from 7-monthold MPS IIIB mice, compared to wild-type (WT) mice. The metabolic disturbances involve virtually all major pathways of amino acid, peptide (58/102), carbohydrate (18/28), lipid (111/139), nucleotide (12/24), energy (2/9), vitamin and cofactor (11/16), and xenobiotic (11/28) metabolism. Notably, the reduced metabolites included eight essential amino acids, vitamins (C, E, B2, and B6), and neurotransmitters (serotonin, glutamate, aspartate, tryptophan, and N-acetyltyrosine). The metabolic impairments appear to emerge early during disease progression before the age of 2 months. Importantly, the restoration of NAGLU activity with an intravenous (i.v.) injection of rAAV9-hNAGLU vector led to near-complete correction of all serum metabolite abnormalities, with 201 (87%) metabolites normalized and 30 (13%) over-corrected. While the mechanisms are unclear, our data demonstrate that the lack of NAGLU activity triggers profound functional metabolic disturbances in MPS IIIB. These metabolic impairments respond well to a systemic rAAV9-hNAGLU gene delivery, supporting the surrogate biomarker potential of serum metabolomic profiles for MPS IIIB therapies.

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“…34,35 H&E was performed using undiluted hematoxylin (Gill's #2; Electron Microscopy Sciences, Fort Washington, PA, USA) followed by immersion in a working solution of 0.3% eosin. 5,36 For AO staining, tissue sections were placed in a 0.2 M dibasic sodium phosphate/0.1 M citric acid (SC; pH 4.0) solution for 5 min prior to staining with AO (10 mg/ ml) in SC buffer for 15 min. The sections were rinsed three times in SC buffer and immersed briefly in 50% ethanol in 0.1 M Tris.…”

Section: Histochemical and Immunocytochemical Preparationmentioning

confidence: 99%

Combined histochemical staining, RNA amplification, regional, and single cell cDNA analysis within the hippocampus

Ginsberg

Che

2004

Laboratory Investigation

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The use of five histochemical stains (cresyl violet, thionin, hematoxylin & eosin, silver stain, and acridine orange) was evaluated in combination with an expression profiling paradigm that included regional and single cell analyses within the hippocampus of post-mortem human brains and adult mice. Adjacent serial sections of human and mouse hippocampus were labeled by histochemistry or neurofilament immunocytochemistry. These tissue sections were used as starting material for regional and single cell microdissection followed by a newly developed RNA amplification procedure (terminal continuation (TC) RNA amplification) and subsequent hybridization to custom-designed cDNA arrays. Results indicated equivalent levels of global hybridization signal intensity and relative expression levels for individual genes for hippocampi stained by cresyl violet, thionin, and hematoxylin & eosin, and neurofilament immunocytochemistry. Moreover, no significant differences existed between the Nissl stains and neurofilament immunocytochemistry for individual CA1 neurons obtained via laser capture microdissection. In contrast, a marked decrement was observed in adjacent hippocampal sections stained for silver stain and acridine orange, both at the level of the regional dissection and at the CA1 neuron population level. Observations made on the cDNA array platform were validated by realtime qPCR using primers directed against b-actin and glyceraldehyde-3 phosphate dehydrogenase. Thus, this report demonstrated the utility of using specific Nissl stains, but not stains that bind RNA species directly, in both human and mouse brain tissues at the regional and cellular level for state-of-the-art molecular fingerprinting studies.

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Accumulation of Intracellular Amyloid-β Peptide (Aβ 1–40) in Mucopolysaccharidosis Brains

Cited by 59 publications

References 0 publications

Sanfilippo syndrome type B, a lysosomal storage disease, is also a tauopathy

Sanfilippo syndrome type B, a lysosomal storage disease, is also a tauopathy

Near-Complete Correction of Profound Metabolomic Impairments Corresponding to Functional Benefit in MPS IIIB Mice after IV rAAV9-hNAGLU Gene Delivery

Combined histochemical staining, RNA amplification, regional, and single cell cDNA analysis within the hippocampus

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