heparitin-sulfate and Down-Syndrome

Alterations of the cerebral microvasculature have been reported in aging and in neurodegenerative disorders such as Alzheimer's disease. However, the exact role of microvascular alterations in the pathogenesis of neurodegeneration remains unknown. In the present report, the cerebral cortex microvasculature was studied by immunohistochemistry using a monoclonal antibody against vascular heparan sulfate proteoglycan protein core in normal aging controls. Alzheimer's disease, Down syndrome, Guam amyotrophic lateral sclerosis/parkinsonian dementia complex, Pick's disease and dementia pugilistica. In all dementing illnesses, increased microvascular pathology was evident compared to normal controls. Decreased microvascular density and numerous atrophic vessels were the primary abnormalities observed in all dementing disorders. These microvascular abnormalities demonstrated regional and laminar selectivity, and were primarily found in layers III and V of frontal and temporal cortex. Quantitative analysis employing computer-assisted microscopy demonstrated that the decrease in microvascular density in Alzheimer's disease was statistically significant compared to age-matched controls. In addition, extracellular heparan sulfate proteoglycan deposits were observed which colocalized with thioflavine S-positive senile plaques in Alzheimer's disease, Down syndrome and selected Guam dementia cases. In some cases, heparan sulfate proteoglycan was seen in senile plaques that appeared to be diffuse or primitive plaques that stained weakly with thioflavine. Heparan sulfate proteoglycan-containing neurons were also observed in Alzheimer's disease, as well as in Down syndrome and Guam cases. Glial staining for heparan sulfate proteoglycan was never observed. Our data support previous observations that microvascular pathology is found in aging and in Alzheimer's disease. The changes in Alzheimer's disease exceed those found in normal aging controls. We also found microvascular pathology in all other dementing disorders studied. Our studies further demonstrated that the microvascular pathology displays regional and laminar patterns which parallel patterns of neuronal loss. Finally, we also found that heparan sulfate proteoglycan is present in senile plaques and neurons not only as previously reported in Alzheimer's disease, but also in Down syndrome and Guam cases. Heparan sulfate proteoglycan in senile plaques may be derived from either the degenerating microvasculature or fro

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Blood Vessels; Cerebrovascular Circulation; Dementia; Down Syndrome; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Microcirculation; Middle Aged; Proteoglycans; Reference Values

As early as 1928, Cajal suggested that plaques contain a trophic substance which attracts neurites. Recently, basic fibroblast growth factor (bFGF) levels were shown to be elevated in Alzheimer's disease (AD) and localized to plaques and neurofibrillary tangles. We sought to clarify the subtype of plaques which contain bFGF and provide more detail on bFGFs neuronal and vascular localization in normal aged brain, AD brain, and Down's syndrome (DS) brain. We combined double-labeling immunocytochemistry for bFGF with heparan sulfate glycosaminoglycans, beta-amyloid, and thioflavine fluorescence. In addition, the neuritic markers tau-1 and PHF-1 were combined with bFGF staining. Eleven AD, five nondemented controls, and four DS cases were examined. Most bFGF immunopositive plaques contained numerous dystrophic fibers, indicating they were of the neuritic subtype. We also detected a variety of bFGF-positive cells, including hilar, dentate granule, pyramidal, and stellate neurons, as well as astrocytes. The basement membrane of large and small arterioles also contained bFGF. bFGF immunoreactivity within neurons, astrocytes and the vasculature was increased in AD cases relative to controls. Immunoreactivity within the DS cases was intermediate. These results suggest that bFGF is up-regulated in AD and support the hypothesis that bFGF may attract neurites into plaques. Alternatively, an injured neurite may induce bFGF production by responding glia, resulting in further neuritic attraction.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Antibodies, Monoclonal; Benzothiazoles; Biomarkers; Child; Child, Preschool; Down Syndrome; Fibroblast Growth Factor 2; Fluorescent Dyes; Heparitin Sulfate; Humans; Immunohistochemistry; Middle Aged; Nerve Fibers; Neurites; Neurofibrillary Tangles; Thiazoles

A monoclonal antibody (HK-249) that recognizes a glucosamine sulfate alpha 1----4 glucuronic acid-containing determinant in heparan sulfate (HS) chains of a basement membrane-derived heparan sulfate proteoglycan identified and immunolocalized HS specifically to the amyloid deposits in neuritic plaques (NPs), congophilic angiopathy (CA), as well as in neurofibrillary tangles (NFTs) and non-tangle-bearing neurons in the brains of Alzheimer's and Down's syndrome (DS) patients. Ultrastructural immunohistochemistry demonstrated that HS within neurons of Alzheimer's disease (AD) brain was localized to lipofuscin granules, an aging pigment previously shown also to contain beta-amyloid protein (BAP). Heparan sulfate also was localized to neurite-containing, nonfibrillar 'primitive' plaques that also demonstrated positive BAP immunoreactivity in both AD and DS brains. Antibodies to laminin, fibronectin, and a chondroitin sulfate proteoglycan failed to show positive immunostaining of the HS-containing sites described above. Analysis of DS patients at different ages revealed that HS accumulated within neurons of the hippocampus and amygdala as early as 1 day after birth. Young age-matched controls did not demonstrate similar positive HS immunoreactivity in neurons, whereas positive immunostaining for HS was observed in other regions thought to normally contain HS. The earliest deposition of BAP was first observed as 'amorphous' or 'diffuse' cortical deposits in DS brain in patients aged 18 and 24 years before the accumulation of fibrillar amyloid (observed in DS patients who are 35 years and older). These cortical deposits also contained positive HS immunoreactivity, implying that HS accumulation in conjunction with the BAP is an early event that ultimately may contribute to the early age-related accumulation (ie, as early as 35 years of age in DS) of NPs, NFTs, and/or CA. Furthermore the colocalization of HS and BAP in a number of specific locales in AD and DS brain indicates a possible interaction between these two macromolecules that may be important in lesion development in these two diseases.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amygdala; Amyloid beta-Peptides; Autopsy; Biomarkers; Brain; Cerebellum; Child; Child, Preschool; Down Syndrome; Female; Heparitin Sulfate; Hippocampus; Humans; Immunohistochemistry; Infant; Infant, Newborn; Male; Microscopy, Immunoelectron; Middle Aged; Neurons