ABSTRACT
Mutations within the Abeta sequence of the AbetaPP gene are associated with familial forms of cerebral amyloid angiopathy (CAA). One mutation, Abeta D23N, was identified in a family in Iowa with a clinical history of early-onset dementia. We analyzed the pattern of Abeta deposition in the hippocampus of an individual with Iowa CAA. In addition to strong amyloid angiopathy, we found unusual diffuse Abeta deposits in the CA4, and in the parenchyma near amyloid-laden vessels. ELISA of cortical brain extracts showed that Abeta40 was nearly 20-fold higher than Abeta42, in both soluble and insoluble fractions. We identified an Abeta antibody that recognized wild-type Abeta but not Iowa Abeta. With this antibody, we found that wild-type Abeta was present in the Abeta deposits, but limited to the strongest deposits in the cerebrovasculature. Previous in vitro studies suggested that the presence of an asparagine at position 23 of Abeta favored formation of an isoAsp residue, which was associated with increased Abeta fibrillogenesis. Using isoAsp-specific antibodies in immunohistochemical studies, we examined the distribution of isoAsp Abeta in the Iowa brain. IsoAsp7 Abeta was present in both the parenchymal and vascular deposits, whereas isoAsp23 Abeta was present only in vascular deposits. These data suggest that alteration of Abeta Asn23 to isoAsp may be an important determinant in the deposition of Abeta in cerebral blood vessels.
Subject(s)
Amyloid beta-Peptides/metabolism , Blood Vessels/pathology , Cerebral Amyloid Angiopathy, Familial/metabolism , Amyloid beta-Peptides/analysis , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/genetics , Amyloid beta-Peptides/immunology , Antibodies , Blood Vessels/metabolism , Brain/metabolism , Brain/pathology , Cerebral Amyloid Angiopathy, Familial/genetics , Cerebral Amyloid Angiopathy, Familial/immunology , Enzyme-Linked Immunosorbent Assay , Hippocampus/blood supply , Hippocampus/immunology , Hippocampus/metabolism , Humans , Immunohistochemistry , Iowa , Isoaspartic Acid , MutationABSTRACT
Vascular dysfunction due to cerebral amyloid angiopathy (CAA) may contribute to cognitive impairment. The Iowa D694N amyloid precursor protein mutation, a recently identified cause of hereditary CAA with dementia, offers an opportunity to explore the anatomic basis of CAA-related vascular dysfunction. Examination by immunolabeling and confocal microscopy demonstrated extensive loss of smooth muscle cells in affected segments as well as a perivascular inflammatory reaction of astrocytes and microglia. On 3-D reconstruction, vessels appeared tortuous with twiglike projections that may represent areas of vascular degeneration. The observed changes in the Iowa brain suggest pathophysiologic mechanisms for vascular dysfunction in CAA and possible approaches to treatment of CAA-related cognitive impairment.
Subject(s)
Cerebral Amyloid Angiopathy, Familial/pathology , Muscle, Smooth, Vascular/pathology , Temporal Lobe/blood supply , Humans , Iowa , Microcirculation/pathology , Microcirculation/ultrastructure , Temporal Lobe/pathologyABSTRACT
A recent genetic study demonstrated associations between an altered risk of Alzheimer's disease (AD) and two polymorphisms in the lipoprotein lipase (LPL) gene, Asn291Ser and Ser447Ter. LPL immunostains senile plaques, and is a ligand of the low-density lipoprotein receptor-related protein (LRP), a major apolipoprotein E (apoE) receptor. LPL increases the cellular uptake of apoE via LRP, and polymorphisms in LPL alter its ability to mediate apoE-LRP interactions, with potential implications for AD pathogenesis. Here, we tested the genetic association of LPL with AD in a case-control study. For the Asn291Ser polymorphism, we analyzed 277 individuals (141 AD, 136 control) and found no significant difference in allele frequencies between the AD and control groups. For the Ser447Ter polymorphism, we analyzed 187 individuals (108 AD, 79 control) and again found no significant difference in allele frequencies between the AD and control groups. Thus, our study does not support associations between AD and two common polymorphisms in LPL.
