Cultured cell and transgenic mouse models for tau pathology linked to beta-amyloid.
The two histopathological signatures of Alzheimer's disease (AD) are amyloid plaques and neurofibrillary tangles, prompting speculation that a causal relationship exists between the respective building blocks of these abnormal brain structures: the beta-amyloid peptides (Abeta) and the neuron-enriched microtubule-associated protein called tau. Transgenic mouse models have provided in vivo evidence for such connections, and cultured cell models have allowed tightly controlled, systematic manipulation of conditions that influence links between Abeta and tau. The emerging evidence supports the view that amyloid pathology lies upstream of tau pathology in a pathway whose details remain largely mysterious. In this communication, we review and discuss published work about the Abeta-tau connection. In addition, we present some of our own previously unpublished data on the effects of exogenous Abeta on primary brain cultures that contain both neurons and glial cells. We report here that continuous exposure to 5 microM non-fibrillar Abeta40 or Abeta42 kills primary brain cells by apoptosis within 2-3 weeks, Abeta42 is more toxic and selective for neurons than Abeta40, and Abeta42, but not Abeta40, induces a transient increase in neurons that are positive for the AD-like PHF1 epitope. These findings demonstrate the greater potency of Abeta42 than Abeta40 at inducing tau pathology and programmed cell death, and corroborate and extend reports that tau-containing cells are more sensitive to Abeta peptides than cells that lack or express low levels of tau.
Bloom
George S
GS
Departments of Biology, and Cell Biology, University of Virginia, Charlottesville, VA 22903, USA. gsb4g@virginia.edu
Ren
Ke
K
Glabe
Charles G
CG
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D024801:Tauopathies / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics*
D016229:Amyloid beta-Peptides; D016875:tau Proteins