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Overexpression of heparanase lowers the amyloid burden in amyloid-? precursor protein transgenic mice.

ABSTRACT: Heparan sulfate (HS) and HS proteoglycans (HSPGs) colocalize with amyloid-? (A?) deposits in Alzheimer disease brain and in A? precursor protein (A?PP) transgenic mouse models. Heparanase is an endoglycosidase that specifically degrades the unbranched glycosaminoglycan side chains of HSPGs. The aim of this study was to test the hypothesis that HS and HSPGs are active participators of A? pathogenesis in vivo. We therefore generated a double-transgenic mouse model overexpressing both human heparanase and human A?PP harboring the Swedish mutation (tgHpa*Swe). Overexpression of heparanase did not affect A?PP processing because the steady-state levels of A?1-40, A?1-42, and soluble A?PP ? were the same in 2- to 3-month-old double-transgenic tgHpa*Swe and single-transgenic tgSwe mice. In contrast, the Congo red-positive amyloid burden was significantly lower in 15-month-old tgHpa*Swe brain than in tgSwe brain. Likewise, the A? burden, measured by A?x-40 and A?x-42 immunohistochemistry, was reduced significantly in tgHpa*Swe brain. The intensity of HS-stained plaques correlated with the A?x-42 burden and was reduced in tgHpa*Swe mice. Moreover, the HS-like molecule heparin facilitated A?1-42-aggregation in an in vitro Thioflavin T assay. The findings suggest that HSPGs contribute to amyloid deposition in tgSwe mice by increasing A? fibril formation because heparanase-induced fragmentation of HS led to a reduced amyloid burden. Therefore, drugs interfering with A?-HSPG interactions might be a potential strategy for Alzheimer disease treatment.

SUBMITTER: Jendresen CB

PROVIDER: S-EPMC4335241 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Overexpression of heparanase lowers the amyloid burden in amyloid-β precursor protein transgenic mice.

Jendresen Charlotte B CB Cui Hao H Zhang Xiao X Vlodavsky Israel I Nilsson Lars N G LNG Li Jin-Ping JP

The Journal of biological chemistry 20141229 8

Heparan sulfate (HS) and HS proteoglycans (HSPGs) colocalize with amyloid-β (Aβ) deposits in Alzheimer disease brain and in Aβ precursor protein (AβPP) transgenic mouse models. Heparanase is an endoglycosidase that specifically degrades the unbranched glycosaminoglycan side chains of HSPGs. The aim of this study was to test the hypothesis that HS and HSPGs are active participators of Aβ pathogenesis in vivo. We therefore generated a double-transgenic mouse model overexpressing both human heparan ...[more]

PMID: 25548284

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Project description:BackgroundThe deposition of the amyloid β-peptide (Aβ) in the brain is one of the hallmarks of Alzheimer's disease (AD). It is not yet clear whether Aβ always leads to similar changes or whether it induces different features of neurodegeneration in relation to its intra- and/or extracellular localization or to its intracellular trafficking routes. To address this question, we have analyzed two transgenic mouse models: APP48 and APP23 mice. The APP48 mouse expresses Aβ1-42 with a signal sequence in neurons. These animals produce intracellular Aβ independent of amyloid precursor protein (APP) but do not develop extracellular Aβ plaques. The APP23 mouse overexpresses human APP with the Swedish mutation (KM670/671NL) in neurons and produces APP-derived extracellular Aβ plaques and intracellular Aβ aggregates.ResultsTracing of commissural neurons in layer III of the frontocentral cortex with the DiI tracer revealed no morphological signs of dendritic degeneration in APP48 mice compared to littermate controls. In contrast, the dendritic tree of highly ramified commissural frontocentral neurons was altered in 15-month-old APP23 mice. The density of asymmetric synapses in the frontocentral cortex was reduced in 3- and 15-month-old APP23 but not in 3- and 18-month-old APP48 mice. Frontocentral neurons of 18-month-old APP48 mice showed an increased proportion of altered mitochondria in the soma compared to wild type and APP23 mice. Aβ was often seen in the membrane of neuronal mitochondria in APP48 mice at the ultrastructural level.ConclusionsThese results indicate that APP-independent intracellular Aβ accumulation in APP48 mice is not associated with dendritic and neuritic degeneration but with mitochondrial alterations whereas APP-derived extra- and intracellular Aβ pathology in APP23 mice is linked to dendrite degeneration and synapse loss independent of obvious mitochondrial alterations. Thus, Aβ aggregates in APP23 and APP48 mice induce neurodegeneration presumably by different mechanisms and APP-related production of Aβ may, thereby, play a role for the degeneration of neurites and synapses.

Dataset Information

Overexpression of heparanase lowers the amyloid burden in amyloid-? precursor protein transgenic mice.

Publications

Overexpression of heparanase lowers the amyloid burden in amyloid-β precursor protein transgenic mice.

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