Perspective on the calcium dyshomeostasis hypothesis in the pathogenesis of selective neuronal degeneration in animal models of Alzheimer's disease

Alzheimer’s disease (AD) is a neurodegenerative disease associated with the abnormal accumulation of amyloid b (Ab) and microtubule-associated protein tau (tau). Although the mechanisms through which abnormal accumulation of proteins leads to neuronal vulnerability are still under investigation, intracellular calcium homeostasis is dysregulated and has been implicated in the neurobiology of AD [1–6]. Mouse models of neurodegenerative diseases have been used to investigate the proteins associated with neurodegenerative diseases, including Ab. These animal models have lead to invaluable insight into the mechanisms and progression of the diseases. A number of animal models of AD have been created [7]. Calcium dysregulation has been proposed as a mechanism through which aggregated Abmay lead to neurodegeneration [1,8]. Two-photon microscopy is a powerful imaging tool used to acquire neural data in vivo and has been used to capture and analyze changes in calcium signaling in various models of AD. Previous reports have used in vivo twophoton imaging in awake behaving mice to show that altered calcium homeostasis in amyloid precursor protein (APP) tg mice was associated with Ab plaques [9,10], but not in anesthetized PS1 tg animal models [11], or neurofibrillary tangle–bearing neurons in a tau (P301L) mutant model [12]. Moreover, a recent study using patch clamping and twophoton imaging confirms alterations in APP/PS1 but found that these alterations are independent of plaques [13]. A recent study characterizing multiple animal models of neurodegeneration found abnormal calcium dynamics in a mouse model of AD [14]. Specifically, the normalized 1-Hz stimulus-driven neural calcium transients exhibited anomalous features in their geometric shapes (Fig. 1). Temporal signal variations were analyzed using statistical measures of