Analyses of the Link Between Amyloid and Tau Pathology in an AD Mouse Model (3xtg-AD): Disease Progression with Increased Levels of Abeta and Tau Peptides
Zapata, Lucio, Jr.
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INTRODUCTION: Pathological features of Alzheimer's disease (AD) include the accumulation of extracellular amyloid plaques composed of aggregated amyloid-β (Aβ) peptide and intracellular neurofibrillary tangles consisting of phosphorylated tau protein. Mutations in the genes that encode amyloid precursor protein (APP), and presenilin 1 and 2 (PS1/PS2) have been shown to cause familial AD in humans. Studies provided evidence that Aβ accumulation may initiate phosphorylation of tau protein, via the Ras/MEK/Extracellular Signal-regulated Kinase (ERK) signaling cascade, activation of the mitogen-activated protein kinase (p38 MAPK), Cyclin dependent kinase 5 (CDK5) and/or glycogen synthase kinase-3β (GSK3β). We studied distribution of Aβ and tau oligomers, Erk activity in different brain lysate fractions from different age groups of a triple transgenic mouse model (3xTg-AD) and wild-type mice, and Erk activity in DNA Abeta42 immunized mice. METHODS: Brain lysates of 4-, 6-, 12-, and 20-month-old 3xTg-AD and wild-type mice were prepared via a 4-step extraction protocol in TBS (soluble), TBS-T, SDS, and formic acid. DNA Abeta42 vaccination administered via gene gun. Abeta and Tau concentrations and Tau phosphorylation levels were monitored by Dot blot, Semidenaturing detergent agarose gel electrophoresis (SDD-AGE), and ELISA using anti-Abeta and anti-Tau antibodies. Erk1/2 levels were monitored by Western blot using monoclonal antibodies. RESULTS: There was a significant increase of total tau concentrations with increasing age and we found also an increasing insolubility (more tau in the non-soluble brain lysate fractions). 4- and 20-month-old 3xTg-AD soluble brain lysates indicated the presence of aggregated tau peptide, which was not present in wild-type control mice. Kinases involved with tau phosphorylation were measured and showed an increase of activated/phosphorylated Erk1/2 with increasing age, with a drop in concentration at 12 months in half of the mice analyzed (n=5). Immunized 3xTg-AD mice showed a decrease in activated Erk1/2 when compared to non-immunized, age matched mice. DISCUSSION: The 3xTg-AD mouse model provides a good model to study pathologies and possible treatments for human Alzheimer's disease. Abeta 42 peptide and tau increase due to age in this mouse model. A link between the amyloid pathology is likely found in the wide spectrum of cellular kinases which are upregulated due to Abeta in Alzheimer's disease. Therefore, immunization against Abeta and generation of anti-Abeta antibody will indirectly reduce tau pathology.