Premium
O4‐02–01: Interaction of sorLA/LR11 with multiple members of the low‐density lipoprotein receptor family
Author(s) -
Adams Kenneth W.,
Spoelgen Robert,
Andersen Olav M.,
Stoothof Will,
Joyner Daniel,
Strickland Dudley,
Willnow Thomas E.,
Hyman Bradley T.
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.509
Subject(s) - endosome , immunoprecipitation , microbiology and biotechnology , immunocytochemistry , golgi apparatus , ldl receptor , receptor , biology , biophysics , biochemistry , intracellular , lipoprotein , gene , endoplasmic reticulum , endocrinology , cholesterol
and litters until P42. Under this regime we studied the effects of p25 on adult mouse forebrain. We failed to observe any increase in phosphorylation of protein tau and no tauopathy, despite pain-staking analysis at all possible ages. On the other hand, p25 triggered marked neurodegeneration and microgliosis rapidly and intensely in hippocampus and cortex. Progressive neurodegeneration comprised massive neuron loss, causing brain atrophy (40% loss at age 5 months) with nearly complete elimination of the hippocampus. Neurodegeneration did neither involve amyloid peptide generation nor tauopathy. Degenerating neurons did not stain for TUNEL nor for activated caspase-3, but were marked by FluoroJadeB in early stages. This yields no further clues to the actual mechanism of neurodegeneration, because molecular targets of FluoroJadeB are not known, nor is it specific for neurons as in later stages also activated glia cells were marked. Diseased neurons were always closely associated with activated microglia already very early in the disease process, while these subsided in the course of the disease process in parallel with neuron loss. Reversal experiments with re-administration of doxycycline after 6 or 14 weeks of p25 mode, not only effectively suppressed expression of p25 but also neurodegeneration and microgliosis. Primary neurons derived form the p25 mice activated microglial cells in co-culture, demonstrating the secretion of soluble pro-inflammatory factors by the p25 neurons. Conclusions: The inducible p25 mice present a model for neurodegeneration as in hippocampal sclerosis and neocortical degeneration, with important contributions of activated microglia. The hypothesis emerges that p25 neurons activate microglia by producing as yet unknown factors that decrease in concentration as fewer neurons remain to produce them.