Abstract
The pathogenesis of Alzheimer’s disease (AD) is thought to involve acute neurotoxic effects exerted by oligomeric forms of amyloid-β 1-42 (Aβ). Application of Aβ oligomers in physiological concentrations have been shown to transiently elevate internal Ca2+ in cultured astroglia. While the cellular machinery involved has been extensively explored, to what degree this important signalling cascade occurs in organised brain tissue has remained unclear. Here we adapted two-photon excitation microscopy and calibrated time-resolved imaging (FLIM), coupled with patch-clamp electrophysiology, to monitor Ca2+ concentration ([Ca2+]) inside individual astrocytes and principal neurons in acute brain slices. Inside the slice tissue local micro-ejection of Aβ in sub-micromolar concentrations triggered prominent [Ca2+] elevations in an adjacent astrocyte translated as an approximately two-fold increase (averaged over ∼5min) in basal [Ca2+]. This elevation did not spread to neighbouring cells and appeared comparable in amplitude with commonly documented spontaneous [Ca2+] rises in astroglia. Principal nerve cells (pyramidal neurons) also showed Ca2+ sensitivity, albeit to a lesser degree. These observations shed light on the extent and dynamics of the acute physiological effects of Aβ on brain cells in situ, in the context of AD.
Highlights
Extracellular plaques containing insoluble conjugates of amyloid beta1-42 (A 1-42, the amyloid precursor protein (APP) cleavage product) are a classical indicator of Alzheimer’s disease (AD)
We recently reported that local application of purified amyloid- 1-42 (A)1-42 oligomers at physiological concentrations triggered transient Ca2+ elevations in astroglia and, to a lesser degree, in neurons (Drews et al, 2016)
We found that A oligomers did induce significant [Ca2+] elevations in individual astroglia, while having lesser effects in neurons
Summary
Extracellular plaques containing insoluble conjugates of amyloid beta (A 1-42, the amyloid precursor protein (APP) cleavage product) are a classical indicator of Alzheimer’s disease (AD). A has been shown to dysregulate synaptic proteins triggering degeneration of dendritic spines (Spires-Jones and Hyman, 2014), the underlying cellular machinery is poorly understood In this context, acute application of A to brain cells in situ has been an important tool to discern its molecular targets and the metabolic cascades involved in the cellular response (Jo et al, 2011; Wang et al, 2004). It has been previously shown that the A oligomers taken from the cerebrospinal fluid (CSF) of Alzheimer’s patients impair synaptic plasticity in acute brain slices, the effect preventable by the addition of A antibodies (Walsh et al, 2002) It appears that A targets, directly or indirectly, metabotropic glutamate receptors and the prion protein receptor in the synaptic environment, inducing synaptic dysfunction and eventually cell death (Chen et al, 2010; Lauren et al, 2009; Um et al, 2013). Once inside principal neurons, A rapidly enhance excitatory synaptic transmission, likely because of the insertion of Ca2+-permeable AMPA receptors (Whitcomb et al, 2015)
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