Although senile plaques focally disrupt neuronal health, the functional response of astrocytes to Alzheimer's disease pathology is unknown. Using multiphoton fluorescence lifetime imaging microscopy in vivo, we quantitatively imaged astrocytic calcium homeostasis in a mouse model of Alzheimer's disease. Resting calcium was globally elevated in the astrocytic network, but was independent of proximity to individual plaques. Time-lapse imaging revealed that calcium transients in astrocytes were more frequent, synchronously coordinated across long distances, and uncoupled from neuronal activity. Furthermore, rare intercellular calcium waves were observed, but only in mice with amyloid-β plaques, originating near plaques and spreading radially at least 200 micrometers. Thus, although neurotoxicity is observed near amyloid-β deposits, there exists a more general astrocyte-based network response to focal pathology.

Alzheimer’s disease (AD) is characterized by senile plaques and neurodegeneration although the neurotoxic mechanisms have not been completely elucidated. It is clear that both oxidative stress and inflammation play an important role in the illness. The compound curcumin, with a broad spectrum of anti‐oxidant, anti‐inflammatory, and anti‐fibrilogenic activities may represent a promising approach for preventing or treating AD. Curcumin is a small fluorescent compound that binds to amyloid deposits. In the present work we used in vivo multiphoton microscopy (MPM) to demonstrate that curcumin crosses the blood–brain barrier and labels senile plaques and cerebrovascular amyloid angiopathy (CAA) in APPswe/PS1dE9 mice. Moreover, systemic treatment of mice with curcumin for 7 days clears and reduces existing plaques, as monitored with longitudinal imaging, suggesting a potent disaggregation effect. Curcumin also led to a limited, but significant reversal of structural changes in dystrophic dendrites, including abnormal curvature and dystrophy size. Together, these data suggest that curcumin reverses existing amyloid pathology and associated neurotoxicity in a mouse model of AD. This approach could lead to more effective clinical therapies for the prevention of oxidative stress, inflammation and neurotoxicity associated with AD.

Mitochondria contribute to shape intraneuronal Ca²⁺ signals. Excessive Ca²⁺ taken up by mitochondria could lead to cell death. Amyloid beta (Aβ) causes cytosolic Ca²⁺ overload, but the effects of Aβ on mitochondrial Ca²⁺ levels in Alzheimer’s disease (AD) remain unclear. Using a ratiometric Ca²⁺ indicator targeted to neuronal mitochondria and intravital multiphoton microscopy, we find increased mitochondrial Ca²⁺ levels associated with plaque deposition and neuronal death in a transgenic mouse model of cerebral β-amyloidosis. Naturally secreted soluble Aβ applied onto the healthy brain increases Ca²⁺ concentration in mitochondria, which is prevented by blockage of the mitochondrial calcium uniporter. RNA-sequencing from post-mortem AD human brains shows downregulation in the expression of mitochondrial influx Ca²⁺ transporter genes, but upregulation in the genes related to mitochondrial Ca²⁺ efflux pathways, suggesting a counteracting effect to avoid Ca²⁺ overload. We propose lowering neuronal mitochondrial Ca²⁺ by inhibiting the mitochondrial Ca²⁺ uniporter as a novel potential therapeutic target against AD.

Objective To determine the correspondence between uptake of Pittsburgh Compound B (PiB) in life and measures of β-amyloid (Aβ) in postmortem tissue analysis. Patient A 76-year-old man with a clinical diagnosis of dementia with Lewy bodies underwent fluorodeoxyglucose¹⁸F and PiB positron emission tomographic brain scans. Imaging revealed marked region specific binding of PiB and abnormal fluorodeoxyglucose uptake. Intervention Autopsy was performed 3 months after the PiB scan. Results Autopsy confirmed the clinical diagnosis; in addition, there was severe cerebral amyloid angiopathy and only moderate numbers of parenchymal Aβ plaques. Biochemical measures revealed a positive correlation between Aβ levels and regional PiB binding. Conclusion This report confirms that PiB detects Aβ in the living patient and demonstrates that amyloid deposited as cerebral amyloid angiopathy can be the dominant source of signal.