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Tau pathology in AD synapses: eviden...

Henkins, Kristen M.

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Tau pathology in AD synapses: evidence for fragmentation and aggregation, a role for fyn kinase, and synaptic effects of defective axonal transport.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Tau pathology in AD synapses: evidence for fragmentation and aggregation, a role for fyn kinase, and synaptic effects of defective axonal transport./
Author:	Henkins, Kristen M.
Description:	92 p.
Notes:	Source: Dissertation Abstracts International, Volume: 74-03(E), Section: B.
Contained By:	Dissertation Abstracts International74-03B(E).
Subject:	Biology, Neurobiology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3532469
ISBN:	9781267753793

Tau pathology in AD synapses: evidence for fragmentation and aggregation, a role for fyn kinase, and synaptic effects of defective axonal transport.
Henkins, Kristen M.

Tau pathology in AD synapses: evidence for fragmentation and aggregation, a role for fyn kinase, and synaptic effects of defective axonal transport. - 92 p.

Source: Dissertation Abstracts International, Volume: 74-03(E), Section: B.

Thesis (Ph.D.)--University of California, Los Angeles, 2012.

Neurofibrillary tangles formed by hyperphosphorylated tau protein are a poorly understood, but increasingly important component in the study of the progression of Alzheimer's disease (AD). Tau is a microtubule protein that, under normal conditions, is essential in stabilizing microtubules and axonal transport. However, altered forms of tau can create aggregates that accumulate in areas such as the entorhinal cortex and CA1 of the hippocampus, essential areas in learning and memory.

ISBN: 9781267753793Subjects--Topical Terms:

1681328
Biology, Neurobiology.

Tau pathology in AD synapses: evidence for fragmentation and aggregation, a role for fyn kinase, and synaptic effects of defective axonal transport.
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020 $a 9781267753793
035 $a (MiAaPQ)AAI3532469
035 $a AAI3532469
040 $a MiAaPQ $c MiAaPQ
100 1 $a Henkins, Kristen M. $3 2102161
245 1 0 $a Tau pathology in AD synapses: evidence for fragmentation and aggregation, a role for fyn kinase, and synaptic effects of defective axonal transport.
300 $a 92 p.
500 $a Source: Dissertation Abstracts International, Volume: 74-03(E), Section: B.
500 $a Adviser: Karen Gylys.
502 $a Thesis (Ph.D.)--University of California, Los Angeles, 2012.
520 $a Neurofibrillary tangles formed by hyperphosphorylated tau protein are a poorly understood, but increasingly important component in the study of the progression of Alzheimer's disease (AD). Tau is a microtubule protein that, under normal conditions, is essential in stabilizing microtubules and axonal transport. However, altered forms of tau can create aggregates that accumulate in areas such as the entorhinal cortex and CA1 of the hippocampus, essential areas in learning and memory.
520 $a To date, a comprehensive exploration of the peptide species of tau in the AD synapse has not been performed. Our present experiment uses postmortem human tissue and various tau and p-tau antibodies (including HT7, AT8, pS422, and PHF-1) to categorize the peptide species of tau and phosphorylated tau found in the human synapse by flow cytometry and western blot of synaptosome-enriched samples from normal cases (n=4), neurologic controls (n=3) and AD cases (n=7). Phosphorylation at multiple tau epitopes accompanies amyloid beta (Abeta) pathology, with a fraction (35% of terminals) positive for tau phosphorylated at Ser422, as analyzed by flow cytometry. Abeta-positive synaptic terminals collected by flow sorting show a marked accumulation of p-tau aggregates, and western blots reveal SDS-stable tau oligomers in the dimer/trimer size range in AD samples. Additionally, several tau fragments are synapse-associated in AD, particularly a 20 kDa peptide. Synaptic levels of tau protein are high, with 82% of terminals positive in cognitively normal aged controls; however the positive fraction is reduced to 61% in late stage cases (Braak Stage VI). Tau reduction, taken together with accumulation of actin and its regulatory protein cofilin, suggests cytoskeletal disruption, similar to actin-rich inclusions that mediate tau neurodegeneration, within AD synapses.
520 $a Using flow cytometry analysis of synaptosomes prepared from post-mortem AD cortex, we have previously demonstrated that synaptic Abeta elevations are accompanied by pathologic changes and are co-localized with p-tau. Using flow cytometry analysis, we also looked at several AD related kinases. In these experiments, synaptosomes from our cohort of AD cases and normal controls were immunolabeled with an antibody directed against fyn kinase and immunolabeling was quantified by flow cytometry. AD cases (28.18% positive +/- 5.53, n =4) demonstrated elevated fyn labeling compared to aged normal control cases (8.38% positive +/- 1.62, n = 3, p<0.05).
520 $a It is postulated that tau plays a role in the dendritic localization of fyn kinase. We also examined fyn kinase levels in pre- versus post-synaptic elements from post mortem human tissue which may, in turn, affect the phosphorylation of the post synaptic NMDA receptor. Notably, in late stage AD cases, there was a significant increase in fyn kinase levels in the post-synapse (31.19% +/- 7.03; n=4) versus the pre-synapse (15.87% +/- 3.49; n=4); p<0.005). Similarly, fyn kinase levels were significantly increased in post-synaptic elements (23.62 RFU +/- 7.23; n=5) as compared to pre-synaptic elements (15.70 RFU 0.98; n=5; p<0.05) in inducible tau (Tg4510) mice. Conversely fyn levels were significantly higher in pre-synaptic (33.80 RFU +/-3.04; n=4) compared to post-synaptic elements (17.52 RFU +/- 3.41; n=4; p<0.001) in synaptosomes from aged (20mo.) tau KO mice. Post-synaptic fyn kinase localization may affect downstream, NMDA-dependent cytotoxic cascades.
520 $a These results indicate an increase in synaptic tau that is related to pathogenic aging in Alzheimer's disease, as well as a shift in the peptide species to small fragments and aggregates of tau and phosphorylated tau present in the AD synapse as compared to normal tissue. Our data also supports an in vivo relationship between fyn, Abeta, and tau in Alzheimer's (a 'toxic triad'), and suggests a role for this kinase in tau phosphorylation and a synaptic amyloid cascade in human disease and transgenic models.
590 $a School code: 0031.
650 4 $a Biology, Neurobiology. $3 1681328
690 $a 0421
710 2 $a University of California, Los Angeles. $b Neuroscience. $3 2101050
773 0 $t Dissertation Abstracts International $g 74-03B(E).
790 $a 0031
791 $a Ph.D.
792 $a 2012
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3532469