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[P4–130]: β‐AMYLOID SYNAPTOTOXICITY DRIVES β‐AMYLOID PRODUCTION
Author(s) -
Killick Richard,
Elliott Christina,
Sellers Katherine,
Alshawi Raya,
Simons J Paul,
Ghosh Anshua,
Jackson Joshua,
Harte Michael,
Hooper Nigel,
Srivastava Deepak,
Lovestone Simon
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.06.1996
Subject(s) - wnt signaling pathway , fasudil , dkk1 , rhoa , downregulation and upregulation , genetically modified mouse , amyloid precursor protein , microbiology and biotechnology , chemistry , medicine , endocrinology , pharmacology , signal transduction , neuroscience , transgene , biology , alzheimer's disease , rho associated protein kinase , biochemistry , disease , gene
Background:Vascular contributions to cognitive impairment and dementia (VCID) are common in older people. Cerebral small vessel disease (SVD) is a common cause of VCID (Esiri et al., 1997). The molecular mechanisms that link vascular pathology with parenchymal damage and cognitive impact are not well understood. Here we investigated the distribution of axonal damage and of phosphorylated neurofilament proteins. Methods: Subcortical white matter samples were taken from frontal and parietal cerebral cortices of older people (age range: 69-95 y, n1⁄422) with absent/minimal Alzheimer’s disease (AD) pathology (Braak stage < IV). Sections were labelled immunohistochemically with a phosphorylation-selective neurofilament antibody (p-NF). Neighbouring sections were labelled with pan-selective neurofilament antibody. In scanned sections the extent of immunolabelling (% area fraction) was determined using a densitometry algorithm (Bridges et al., 2014). Results: Areas of strongly positive axonal p-NF immunolabelling was seen in all older cases, and revealed axonal bulbs and an orientation around small vessels of arterial appearance. Labelling with pan-selective neurofilament antibody indicated that only a subset of axons were p-NF positive. Equivalent brain areas from young people showed very little p-NF immunolabelling. A case with Stiff Man syndrome (male, age 40 y) exhibited extensive axonal p-NF labelling and axonal bulbing, without a vasculo-centric staining pattern. The degree of bulbing and of vasculo-centricity for each section were assigned a simple categorical score (0-7). Degree of axonal bulbing was highly associated with vasculocentricity score (Spearman rho1⁄40.963, p<0.001) and with the extent (% area fraction) of p-NF labelling (rho1⁄40.763, p<0.001). Conclusions: Axonal neurofilament phosphorylation within subcortical white matter was associated with axonal bulbing and displayed a vasculo-centric distribution in AD-free older people. References: Bridges LR, Andoh J, Lawrence AJ, Khoong CH, Poon WW, Esiri MM, Markus HS, Hainsworth AH. J Neuropathol Exp Neurol. 2014. 73: 1026-33. Blood-brain barrier dysfunction and cerebral small vessel disease (arteriolosclerosis) in brains of older people. Esiri MM, Wilcock GK, Morris JH. J Neurol Neurosurg Psychiatry. 1997. 63: 749-53. Neuropathological assessment of the lesions of significance in vascular dementia.