09 April 2008
Alzheimer's and Neurofibrillary Tangles
The articles we have read about Alzheimer's have focused on the amyloid-beta pathology. The other part of Alzheimer's disease is the formation of neurofibrillary tangles. Neurofibrillary tangles are composed of tau proteins that have abnormally formed because of overactive enzymes. Tau proteins are a microtubule associated protein. Tau proteins are important for assembling tubulin monomers into microtubules. Tau proteins also serve a structural purpose by maintaining the cytoskeleton and helping axonal transport. Neurofibrillary tangles form when there is a hyper-phosphorylation of tau protein and it becomes insoluble and forms aggregates. The tangles result in the death of cells and this is the role is plays in Alzheimer's disease.
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What causes the hyper-phosphorylation of the Tau proteins? If theres a way to prevent (or reverse) the hyper-phosphorylation then that could be one way to reduce neurofibrillary tangles (another way to prevent AD).
I found an interesting article that link ApoE to hyper-phosphorylation of the Tau proteins.
Researchers from the Flemish Institute of Biotechnology in Leuven, Belgium, believe the expression of human apolipoprotein E4 (ApoE4) in neurons cause hyperphosphorylation of protein Tau in the brains of transgenic mice. They studied the effects of ApoE overexpression in different brain cell types using 4 distinct promoter constructs.
ApoE proteins have been found in human hippocampus neurons of AD patients and aged individuals. Recent studies have demonstrated that the human brain neurons can synthesize ApoE. According to epidemiological studies, the epsilon 4 allele of the ApoE gene is associated with a late onset and sporadic AD. Also, increased ApoE mRNA has been observed in brains of AD patients. This allele has been associated with poor neurological recovery, cerebral hemorrhage, and cognitive status of cardiac bypass surgery. In this study, transgenic mice expressing ApoE4 in neurons under control of the neuron-specific enolase promoter were reported having difficulty with learning in water maze tasks and with exploratory behavior at 6 months
The researchers generated 25 independent founder transgenic mice that overexpress human ApoE4 in neurons and/or astrocytes. They used four different gene promoter constructs derived from the mouse Thy1 gene, the human GFAP gene, the human PDGF-ß gene, or the mouse PGK gene. The initial phenotypic characterization demonstrated strong neuronal expression in the hippocampus and cortex of Thy1-ApoE4 and PDGF-ApoE4 transgenic mice, whereas the PGK-ApoE4 transgenic mice showed neuronal expression over the entire brain. GFAP-ApoE4 transgenic mice expression was restricted to astroglia. With a panel of protein tau-specific antibodies, hyperphosphorylation of the microtubule-associated protein tau became evident
Protein tau phosphorylation was analyzed and compared using four specific monoclonal antibodies (AT8, AT180, PHF1, and TAU5). Western blot analysis of brain homogenates of transgenic mice showed that the microtubule-associated protein tau became hyperphosphorylated in mice expressing ApoE4 in neurons. This was demonstrated in two independent Thy1-ApoE4 transgenic lines. Increases in protein tau phosphorylation appeared in Thy1-ApoE4 line 13 (tae-XIII) transgenic mice of 3 months and was more noticeable in mice of 18 months. In line tae-II, with lower neuronal expression levels, increased protein tau phosphorylation appeared when mice were 7 months old, indicating that hyperphosphorylation of protein tau correlated with neuronal ApoE4 expression levels. After immunoblotting with TAU5 antibody, an obvious decrease in electrophoretical mobility of the protein tau isoforms was observed confirming the increase in phosphorylation of protein tau in the brain of Thy1-ApoE4 transgenic mice. This was demonstrated with antibodies AT8, AT180, and PHF1. When the brain extracts were treated with alkaline phosphatase, dephosphorylation of protein tau was evident and was detected with antibodies AT8 and TAU5. They found that phosphorylation of protein tau was variable at all age groups, however, was higher in transgenic mice relative to age-matched Wt mice.
Two mechanism have been proposed (by the authors) to explain the generic association between ApoE and AD. One mechanism suggests that ApoE interacts with the microtubule-associated protein tau to alter the phosphorylation state and is involved in stabilizing the neuronal cytoskeleton. In the other mechanism ApoE functions as a "pathological chaperone," affecting the clearance of ß-amyloid and causing amyloid deposition.
In any event, according to the authors, ApoE expression in neuronal cells can cause increase hyperphosphorilation of protein tau.
http://ajp.amjpathol.org/cgi/content/full/156/3/951#T1
http://en.wikipedia.org/wiki/Western_blot
http://en.wikipedia.org/wiki/Electrophoretic_mobility_shift_assay
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