https://www.cell.com/neuron/pdf/S0896-6273(12)00756-8.pdf

Synaptic Energy Use and Supply

Oxidative stress and mitochondrial dysfunction in Alzheimer's disease

Mitochondria in Neuroplasticity and Neurological Disorders

Mitochondrial dysfunction has been described in Alzheimer's disease, but how it is induced has remained unclear. Shi Du Yan and her colleagues find that a neurotoxic amyloid protein associated with the disease binds a mitochondrial protein called cyclophilin D and causes neuron death. The authors show that Alzheimer's disease model mice that lack cyclophilin D show improvements in learning and memory. Cyclophilin D (CypD, encoded by Ppif) is an integral part of the mitochondrial permeability transition pore, whose opening leads to cell death. Here we show that interaction of CypD with mitochondrial amyloid-β protein (Aβ) potentiates mitochondrial, neuronal and synaptic stress. The CypD-deficient cortical mitochondria are resistant to Aβ- and Ca2+-induced mitochondrial swelling and permeability transition. Additionally, they have an increased calcium buffering capacity and generate fewer mitochondrial reactive oxygen species. Furthermore, the absence of CypD protects neurons from Aβ- and oxidative stress–induced cell death. Notably, CypD deficiency substantially improves learning and memory and synaptic function in an Alzheimer's disease mouse model and alleviates Aβ-mediated reduction of long-term potentiation. Thus, the CypD-mediated mitochondrial permeability transition pore is directly linked to the cellular and synaptic perturbations observed in the pathogenesis of Alzheimer's disease. Blockade of CypD may be a therapeutic strategy in Alzheimer's disease.

/pdf/cyclophilin-d-deficiency-attenuates-mitochondrial-and-305lraif7o.pdf

Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease.

Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease

A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients.

Evidence for a mitochondrial oxidative phosphorylation defect in brains from patients with schizophrenia

There is increasing evidence that a defect of the mitochondrial respiratory chain is implicated in the development of Parkinson disease. Decreased complex I activity of the mitochondrial respiratory chain has been reported in platelets, muscle, and brain of patients with Parkinson disease. Extrapyramidal symptoms (e.g. parkinsonism and dystonic reactions) are major limiting side effects of neuroleptics. Experimental evidence suggests that neuroleptics inhibit complex I in rat brain. There has not been a study of the effects of neuroleptics in human tissue, however. We therefore analyzed the activities of complexes I + III, complexes II + III, succinate dehydrogenase, complex IV (cytochrome c oxidase), and of citrate synthase in normal human brain cortex after the addition of haloperidol and chlorpromazine and the atypical neuroleptics risperidone, zotepine, and clozapine. Activity of complex I was progressively inhibited by all neuroleptics. Half-maximal inhibition (IC50) was 0.1 mM for haloperidol, 0.4 mM for chlorpromazine, and 0.5 mM for risperidone and zotepine. Clozapine had no effect on enzyme activity at concentrations up to 0.5 mM, followed by a slow decline with a maximum inhibition of 70% at 10 mM. IC50 was at about 2.5 mM. Thus, the concentration of clozapine needed to cause 50% inhibition of the activity of complexes I and III was about 5 times that of zotepine and risperidone, about 6 times that of chlorpromazine, and 25 times that of haloperidol. The inhibition thus paralleled the incidence of extrapyramidal effects caused by the different neuroleptics as they are known from numerous clinical studies. Our data support the hypothesis that neuroleptic-induced extrapyramidal side effects may be due to inhibition of the mitochondrial respiratory chain. (Mol Cell Biochem 174: 255–259, 1997)

Inhibition of complex I by neuroleptics in normal human brain cortex parallels the extrapyramidal toxicity of neuroleptics

Background In orbital myositis, painful diplopia develops owing to an enlargement of the extraocular muscles. Diagnosis is established based on history, clinical manifestations, and therapeutic response to steroids, with the findings of magnetic resonance imaging providing additional information. Observation We observed a family in which 4 members had an ophthalmopathy suggestive of orbital myositis. The affected members are a sibling pair (female and male) and 2 children of the brothers of their father's father. Conclusion The familial incidence suggests a potential genetic predisposition in the development of orbital myositis.

https://jamanetwork.com/journals/jamaneurology/articlepdf/775561/nob7263.pdf

Recurrent orbital myositis: report of a familial incidence.

Mitochordrial respiratory chain enzyme activities were measured in biopsies of left ventricular myocardium from 25 adults In 3 groups: cardiac transplant recipients with atherosclerotic coronary artery disease (CAD), transplant recipients with idiopathic dilated cardiomyopathy (IDC), and patients with compensatory left ventricular hypertrophy due to aortic valve stenosis (AS). Specific activities of complexes 1 + III and II + III were 21 ± 12 and 58 ± 21 nmol/min/mg of noncollagen protein, respectively, in CAD, and 56 ± 21 and 96 ± 57 nmol/min/mg, respectively, in IDC (p

Myocardial respiratory chain enzyme activities in idiopathic dilated cardiomyopathy, and comparison with those in atherosclerotic coronary artery disease and valvular aortic stenosis

Iris Maurer

Papers

A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients.

Evidence for a mitochondrial oxidative phosphorylation defect in brains from patients with schizophrenia

Inhibition of complex I by neuroleptics in normal human brain cortex parallels the extrapyramidal toxicity of neuroleptics

Recurrent orbital myositis: report of a familial incidence.

Myocardial respiratory chain enzyme activities in idiopathic dilated cardiomyopathy, and comparison with those in atherosclerotic coronary artery disease and valvular aortic stenosis