Elsevier

Neuroscience

Volume 159, Issue 3, 31 March 2009, Pages 1055-1069
Neuroscience

Molecular Neuroscience
Vascular amyloid alters astrocytic water and potassium channels in mouse models and humans with Alzheimer's disease

https://doi.org/10.1016/j.neuroscience.2009.01.023Get rights and content

Abstract

The neurovascular unit (NVU) comprises cerebral blood vessels and surrounding astrocytes, neurons, perivascular microglia and pericytes. Astrocytes associated with the NVU are responsible for maintaining cerebral blood flow and ionic and osmotic balances in the brain. A significant proportion of individuals with Alzheimer's disease (AD) have vascular amyloid deposits (cerebral amyloid angiopathy, CAA) that contribute to the heterogeneous nature of the disease. To determine whether NVU astrocytes are affected by the accumulation of amyloid at cerebral blood vessels we examined astrocytic markers in four transgenic mouse models of amyloid deposition. These mouse models represent mild CAA, moderate CAA with disease progression to tau pathology and neuron loss, severe CAA and severe CAA with disease progression to tau pathology and neuron loss. We found that CAA and disease progression both resulted in distinct NVU astrocytic changes. CAA causes a loss of apparent glial fibrillary acidic protein (GFAP)–positive astrocytic end-feet and loss of water channels (aquaporin 4) localized to astrocytic end feet. The potassium channels Kir4.1, an inward rectifying potassium channel, and BK, a calcium-sensitive large-conductance potassium channel, were also lost. The anchoring protein, dystrophin 1, is common to these channels and was reduced in association with CAA. Disease progression was associated with a phenotypic switch in astrocytes indicated by a loss of GFAP-positive cells and a gain of S100β-positive cells. Aquaporin 4, Kir4.1 and dystrophin 1 were also reduced in autopsied brain tissue from individuals with AD that also display moderate and severe CAA. Together, these data suggest that damage to the neurovascular unit may be a factor in the pathogenesis of 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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