Transgenic mouse models for Alzheimer's disease: the role of GSK-3B in combined amyloid and tau-pathology.
Describing and understanding the pathological processes which devastate the brain of Alzheimer's disease (AD) patients remains a major target for experimental biology. We approached this problem by generating different types of single and double transgenic mice that develop pathological hallmarks of AD. In APP-V717 mice, the progression from intracellular amyloid to diffuse and senile plaques with vascular deposits, is preceded by early defects in cognition and LTP. In Tau-P301L mice, the morbid tauopathy with intracellular filaments, cause mortality before age 1 year. Ageing APP-V717IxTau-P301L double tg mice (14-17 months) have combined AD-like pathology in hippocampus and cortex consisting of amyloid plaques and neurofibrillary tangles. Remarkably, while Tau-P301L mice die before age 1 year, the APP-V717IxTau-P301L double tg mice survive much longer, which correlates with alleviation of tauopathy in hindbrain, despite aggravation in forebrain. This hypothesis is corroborated in Tau-P301LxGSK-3B double transgenic mice, which have also an extended lifespan relative to Tau-P301L mice, that correlates with reduction of brainstem tauopathy. At the same time, Tau-P301LxGSK-3B mice have dramatic forebrain tauopathy, with "tangles in almost all neurons", although without hyper-phosphorylation of Tau. The data corroborate the hypothesis that GSK-3B is the missing link between the amyloid and tau-pathology, and position GSK-3B as prominent player in the pathogenesis in AD.
Muyllaert
D
D
Experimental Genetics Group, LEGT-EGG, KULeuven, Campus Gasthuisberg, Leuven, Belgium.
Terwel
D
D
Borghgraef
P
P
Devijver
H
H
Dewachter
I
I
Van Leuven
F
F
D000375:Aging / Q000235:genetics; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D019943:Amino Acid Substitution; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016875:tau Proteins / Q000235:genetics*
D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse