Alzheimer's Disease Cell Biology

Aβ-specific T-cells Reverse Cognitive Decline and Synaptic Loss in Alzheimer’s Mice
Douglas W. Ethella, Daniel Shippy, Chuanhai Cao, Jennifer R. Cracchiolo, Melissa Runfeldt, Brett Blake and Gary W. Arendash,
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Active and passive Aβ immunotherapy each provide behavioral benefits in AD transgenic mice, but they can also induce adverse immune over-activation and neuropathological effects. Here we show that a restricted, Aβ-specific immune re-activation can provide cognitive and pathological benefits to APPsw+PS1 transgenic mice for at least 2½ months. A single infusion of Aβ-specific immune cells from Aβ-vaccinated littermates improved performance in cognitively-impaired APP+PS1 mice. Recipients had lower levels of soluble Aβ in the hippocampus, less plaque-associated microglia, and more intense synaptophysin immunoreactivity, compared with untreated controls. However, Aβ-specific infusates enriched for Th1 or depleted of CD4+ T-cells were not effective, nor were ovalbumin-specific infusates. These benefits occurred without global or brain-specific inflammatory responses. Chronically high levels of Aβ can cause immune tolerance, hypo-responsiveness or anergy to Aβ, but our findings demonstrate that Aβ-specific immune cells can resume endogenous Aβ-lowering processes, and may be an effective Aβ therapeutic.

Decreased neprilysin immunoreactivity in Alzheimer disease, but not in pathological aging
Wang, D. S., Lipton, R. B., Katz, M. J., Davies, P., Buschke, H., Kuslansky, G., Verghese, J., Younkin, S. G., Eckman, C. and Dickson, D. W.
J Neuropathol Exp Neurol (2005) 64: 378-85
One of the proteins involved in the clearing of Abeta is neprilysin. Neprilysin levels are lower than normal in the brains of people with Alzheimer's disease as compared to the brains of normally aged individuals. However, the study shows that lower neprilysin in the brain is unlikely to be the sole cause of increased deposits of Abeta in AD patients.

Dysregulation of Na+/K+ ATPase by amyloid in APP+PS1 transgenic mice
Dickey, C. A., Gordon, M. N., Wilcock, D. M., Herber, D. L., Freeman, M. J. and Morgan, D.
BMC Neurosci (2005) 6: 7
All cells in the brain need systems to control what enters and leaves. A critical element in this control is the balance of salts, particularly sodium and potassium. Changes in a protein that controls this process are closely associated with the presence of the Abeta deposits seen in the brains of mice that develop Alzheimer's disease symptoms.

Dynamic complexity of the microglial activation response in transgenic models of amyloid deposition: implications for Alzheimer therapeutics
Morgan, D., Gordon, M. N., Tan, J., Wilcock, D. and Rojiani, A. M.
J Neuropathol Exp Neurol (2005) 64: 743-53
Inflammation is a normal defense against disease and infection. However, it can be harmful if unchecked. It is certainly one of the many finely balanced systems in the body. The brain has specialized cells, the microglia, that serve as specific immune cells. This review article discusses the roles of microglia and inflammation in Alzheimer's disease and suggests some markers that might be useful in defining the progression of the disease.