Molecular NeuroscienceVascular amyloid alters astrocytic water and potassium channels in mouse models and humans with Alzheimer's disease
Section snippets
Animals
APPSw (Tg2576) mice transgenic for human APP with the Swedish mutation were obtained from K. Hsiao-Ashe (University of Minnesota, MN) (Hsiao et al., 1996). These were crossed to NOS2−/− mice yielding APPSw/NOS2−/− mice as previously described (Colton et al., 2006b). APPSwDI mice were obtained from W. Van Nostrand (Davis et al., 2004). These were crossed to NOS2−/− mice yielding APPSwDI/NOS2−/− mice as previously described (Wilcock et al., 2008). Age-matched littermate NOS2−/− mice and wild-type
Results
To evaluate and compare the specific contributions of CAA alone, disease progression alone and the mixed actions of CAA and disease progression on the observed changes in astrocytes characteristics, we have associated each of the transgenic strains with a level of CAA and with the presence or absence of disease progression. For analysis of the effects of CAA alone, we have compared the APPSw (low CAA levels) to APPSwDI (high CAA levels). These mice strains do not show disease progression. The
Discussion
AD has significant vascular risk factors such as the presence of CAA and microhemorrhage as well as hypertension, diabetes and hypercholesterolemia (de la Torre 2002, Kalaria and Ballard 1999). The NVU is responsible for coupling the cerebral blood flow to local neuronal activity as well as maintaining the ionic and osmotic balances of the surrounding neuronal environment (Abbott et al 2006, Iadecola 2004). In the current study we identify astrocyte changes associated with the NVU in transgenic
Conclusions
Overall, our data point to a critical role for the NVU in AD as has previously been hypothesized (Zlokovic 2005, Iadecola 2004). We have shown in both mouse models of CAA and in humans with AD and CAA that vascular amyloid deposition results in mislocalization of AQP4 expression and changes in expression levels of specific potassium channels, both of which are critical components of physiological systems designed to maintain the brain's external milieu. Disease progression results in altered
Acknowledgments
This work was supported by NIH grants AG030942 (D.M.W.), AG19780 (M.P.V.), AG19740 (C.A.C.). M. P. Vitek is a Principal and Founder of Cognosci, Inc. No financial conflict exists with this study. Human tissue was kindly provided by the Bryan ADRC from the Kathleen Price Bryan Brain Bank (NIA P-30 AG028377).
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