Alpha1-antichymotrypsin, an inflammatory protein overexpressed in Alzheimer's disease brain, induces tau phosphorylation in neurons.

Alpha1-antichymotrypsin, an inflammatory protein overexpressed in Alzheimer's disease brain, induces tau phosphorylation in neurons. Research Abstract Details 

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Alpha1-antichymotrypsin, an inflammatory protein overexpressed in Alzheimer's disease brain, induces tau phosphorylation in neurons. Abstract Text:

Jaya Padmanabhan,Monique Levy,Dennis W Dickson,Huntington Potter,

Amyloid plaques and neurofibrillary tangles are key pathological features of Alzheimer's disease. Alzheimer's disease pathology is also characterized by neuroinflammation and neuronal degeneration, with the proteins associated with inflammatory responses being found in tight association with the plaques. One such protein is the serine protease inhibitor alpha-1-antichymotrypsin (ACT). ACT has been shown to promote Abeta polymerization in vitro and in vivo, and levels of ACT protein in plasma and cerebrospinal fluid from Alzheimer's patients have been found to correlate with progression of dementia. Here we investigated the possible involvement of ACT in tau phosphorylation and tangle formation. As was previously found for Alzheimer's disease, brains from patients with non-Alzheimer's tauopathies exhibited an enhanced expression of ACT, which correlated with the level of tau hyperphosphorylation. Transgenic mice expressing human ACT alone or ACT along with mutant human amyloid precursor protein (APP) showed a significant increase in tau phosphorylation, suggesting that this inflammatory protein can induce tau hyperphosphorylation. The increase in phosphorylation was observed at PHF-1 (P-Ser396/P-Thr404), P-Ser202 and P-Thr231 sites on tau, the P-tau epitopes that are associated with tangles in the patients. This result was further confirmed by the finding that addition of purified ACT induced the same Alzheimer's disease-related tau hyperphosphorylation in cortical neurons cultured in vitro. This correlated with an increase in extracellular signal regulated kinase (ERK) and glycogen synthase kinase-3 activation, indicating their involvement in ACT-induced tau phosphorylation. The ACT-treated neurons showed neurite loss and subsequently underwent apoptosis. Approximately 40-50% of neurons were TUNEL positive by 6 and at 24 h >70% of the neurons showed staining suggesting that ACT was inducing apoptosis in these neurons. These findings indicate that inappropriate inflammatory responses are a potential threat to the brain and that intervention directed at inhibiting the expression or function of ACT could be of therapeutic value in neurodegenerative diseases such as Alzheimer's and other tauopathies.

Alpha1-antichymotrypsin, an inflammatory protein overexpressed in Alzheimer's disease brain, induces tau phosphorylation in neurons. Publishing Authors By Initials

J Padmanabhan,M Levy,DW Dickson,H Potter,

For similar microtubule-associated proteins: tau proteins research abstracts see: microtubule-associated proteins: tau proteins research

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Alpha1-antichymotrypsin, an inflammatory protein overexpressed in Alzheimer's disease brain, induces tau phosphorylation in neurons. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Brain : a journal of neurology

VOLUME: 129

Page Numbers: 3020-34

Journal Abbreviation: Brain

ISSN: 1460-2156

DAY: 20

MONTH: 09

YEAR: 2006

Alpha1-antichymotrypsin, an inflammatory protein overexpressed in Alzheimer's disease brain, induces tau phosphorylation in neurons. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 372537

Alpha1-antichymotrypsin, an inflammatory protein overexpressed in Alzheimer's disease brain, induces tau phosphorylation in neurons. Keywords Mesh Terms:

KEYWORDS: tau Proteins

MESH TERMS: metabolism

Chemical & Substance for Abstract: Alpha1-antichymotrypsin, an inflammatory protein overexpressed in Alzheimer's disease brain, induces tau phosphorylation in neurons. Information

Substance Name: Glycogen Synthase Kinase 3

Registry Number: EC 2.7.1.37

Grant and Affiliation Information for Alpha1-antichymotrypsin, an inflammatory protein overexpressed in Alzheimer's disease brain, induces tau phosphorylation in neurons.

AFFILIATION: The Johnnie B. Byrd Sr. Alzheimer's Center and Research Institute Jacksonville, FL, USA. jpadmana@health.usf.edu

Country: England

AGENCY: United States NIA

GRANT: AG09665

ACRONYM: AG

MEDLINETA: Brain

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