Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer's disease

Mitochondria contribute to shape intraneuronal Ca2+ signals. Excessive Ca2+ taken up by mitochondria could lead to cell death. Amyloid beta (A beta) causes cytosolic Ca2+ overload, but the effects of A beta 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 beta -amyloidosis. Naturally secreted soluble A beta 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. Calvo-Rodriguez et al. show elevated calcium levels in neuronal mitochondria in a mouse model of cerebral beta -amyloidosis after plaque deposition, which precede rare neuron death events in this model. The mechanism involves toxic extracellular A beta oligomers and the mitochondrial calcium uniporter

Loss of cholinergic innervation differentially affects eNOS-mediated blood flow, drainage of Aβ and cerebral amyloid angiopathy in the cortex and hippocampus of adult mice

Vascular dysregulation and cholinergic basal forebrain degeneration are both early pathological events in the development of Alzheimer’s disease (AD). Acetylcholine contributes to localised arterial dilatation and increased cerebral blood flow (CBF) during neurovascular coupling via activation of endothelial nitric oxide synthase (eNOS). Decreased vascular reactivity is suggested to contribute to impaired clearance of β-amyloid (Aβ) along intramural periarterial drainage (IPAD) pathways of the brain, leading to the development of cerebral amyloid angiopathy (CAA). However, the possible relationship between loss of cholinergic innervation, impaired vasoreactivity and reduced clearance of Aβ from the brain has not been previously investigated. In the present study, intracerebroventricular administration of mu-saporin resulted in significant death of cholinergic neurons and fibres in the medial septum, cortex and hippocampus of C57BL/6 mice. Arterial spin labelling MRI revealed a loss of CBF response to stimulation of eNOS by the Rho-kinase inhibitor fasudil hydrochloride in the cortex of denervated mice. By contrast, the hippocampus remained responsive to drug treatment, in association with altered eNOS expression. Fasudil hydrochloride significantly increased IPAD in the hippocampus of both control and saporin-treated mice, while increased clearance from the cortex was only observed in control animals. Administration of mu-saporin in the TetOAPPSweInd mouse model of AD was associated with a significant and selective increase in Aβ40-positive CAA. These findings support the importance of the interrelationship between cholinergic innervation and vascular function in the aetiology and/or progression of CAA and suggest that combined eNOS/cholinergic therapies may improve the efficiency of Aβ removal from the brain and reduce its deposition as CAA

Abnormal synaptic Ca2+ homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice

Paroxysmal Cerebral Disorder

Abnormal Synaptic Morphology and Neuronal Ca2+-Homeostasis in Migraine Mutant Mice

Paroxysmal Cerebral Disorder

Abnormal synaptic morphology and neuronal Ca2+-homeostasis in migraine mutant mice

Assessing neuronal structure and intracellular Ca 2+ levels at baseline, during and after cortical spreading depression in transgenic mice for familial hemiplegic migrain

Comparative Analysis by Magnetic Resonance Imaging of Extracellular Space Diffusion and Interstitial Fluid Flow in the Rat Striatum and Thalamus

Drug delivery to the brain remains a challenge due to the blood-brain barrier. Localized injection of drug therapies represents a promising alternative once the diffusion characteristics of different brain regions have been evaluated. Extracellular space diffusion and interstitial fluid flow of the striatum and thalamus in the rat brain were simultaneously compared using magnetic resonance imaging and the tracer gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA). The diffusion parameters, volume distribution, and half-life time were quantified. While there was extensive diffusion of Gd-DTPA in the striatum, Gd-DTPA was rapidly cleared and had a shorter half-life time in the thalamus. The increased clearance rate and shorter half-life of the tracer in the thalamus were associated with increased expression of Aquaporin-4. The tortuosity of the extracellular space did not show a statistically significant difference between the two regions examined. Our research provides a new reference for brain interstitial drug delivery to treat central nervous system diseases and a better understanding of the brain microenvironment.National Natural Science Foundation of China [81171080, 61450004]; National key developmental program for scientific instrument and equipment [2011YQ030114]; National Science and Technology Pillar Program during the Twelve Five-year Plan Period of China [2012BAI15B009]SCI(E)[email protected]