Biochemical and morphological analyses of Aβ deposits in postmortem brain of Arctic APP mutation carriers
(English)Manuscript (preprint) (Other academic)
The clinical symptoms associated with the Arctic (E693G) mutation in the amyloid-β precursor protein (APP) are those of typical Alzheimer’s disease (AD), beginning with insidious loss of recent memories. However, an unusual neuropathology of ring-like amyloid-β (Aβ) plaques is identified in postmortem brain. Here, the neuropathology of subjects carrying the Arctic mutation was compared to that of sporadic AD. Different types of Aβ-deposits were examined with light, confocal and electron microscopy, and their composition was analyzed with biochemical techniques. Parenchymal deposits of the Arctic mutant brain were homogenous in structure, lacked an amyloid core and were immunostained differentially by antibodies recognizing C- or N-terminal epitopes of Aβ. Superficially, Arctic Aβ plaques bore considerable resemblance to cotton wool plaques (CWP), namely their large size, the presence of healthy neuronal nuclei and the absence of marked neuritic dystrophy within the plaques, and the sparsity of astro- or microgliosis in the surrounding tissue. Both parenchymal deposits and cerebral amyloid angiopathy of Arctic mutant brain contained a mixture of Arctic and wild-type Aβ. While Aβ peptides in parenchymal plaques were often N-terminally truncated, a substantial amount of full-length Aβ1-40 was deposited in the vessel walls as cerebral amyloid angiopathy (CAA). Thus, the absence of amyloid cores in parenchymal plaques of Arctic mutant brain was likely due to the scarcity of full-length Aβ species, although other mechanisms could also be involved. Our findings are discussed in relation to the clinical features of patients carrying the Arctic mutation and neuropathological observations made with other intra-Aβ mutations in human and transgenic mouse brain.
Alzheimer‘s disease, amyloid-β protein, senile plaques, Arctic mutation, Swedish mutation, immunohistochemistry, microscopy, immunoelectron microscopy, mass spectrometry
Public Health, Global Health, Social Medicine and Epidemiology
Research subject Geriatrics
IdentifiersURN: urn:nbn:se:uu:diva-123029OAI: oai:DiVA.org:uu-123029DiVA: diva2:311658
ProjectsPhilipson, Ola. Modeling amyloid-β pathology in Alzheimer´s disease using the Arctic mutation