Converging evidence suggests that the accumulation of cerebral amyloid beta-protein (Abeta) in Alzheimer's disease (AD) reflects an imbalance between the production and degradation of this self-aggregating peptide. Upregulation of proteases that degrade Abeta thus represents a novel therapeutic approach to lowering steady-state Abeta levels, but the consequences of sustained upregulation in vivo have not been studied. Here we show that transgenic overexpression of insulin-degrading enzyme (IDE) or neprilysin (NEP) in neurons significantly reduces brain Abeta levels, retards or completely prevents amyloid plaque formation and its associated cytopathology, and rescues the premature lethality present in amyloid precursor protein (APP) transgenic mice. Our findings demonstrate that chronic upregulation of Abeta-degrading proteases represents an efficacious therapeutic approach to combating Alzheimer-type pathology in vivo.

Currently, ≈1 in 13 people living in the United States has DM, and 90% to 95% of these individuals have type 2 DM (T2DM).2 Overall, the prevalence of T2DM is similar in women and men. In the United States, ≈12.6 million women (10.8%) and 13 million men (11.8%) ≥20 years of age are currently estimated to have T2DM. 2 Among individuals with T2DM, cardiovascular disease (CVD) is the leading cause of morbidity and mortality and accounts for >75% of hospitalizations and >50% of all deaths.3 Although nondiabetic women have fewer cardiovascular events than nondiabetic men of the same age, this advantage appears to be lost in the context of T2DM. 4,5 The reasons for this advantage are not entirely clear but are likely multifactorial with contributions from inherent physiological differences, including the impact of the sex hormones, differences in cardiovascular risk factors, and differences between the sexes in the diagnosis and treatment of DM and CVD. 6 In addition, there are racial and ethnic factors to consider because women of ethnic minority backgrounds have a higher prevalence of DM than non-Hispanic white (NHW) women.This scientific statement was designed to provide the current state of knowledge about sex differences in the cardiovascular consequences of DM, and it will identify areas that would benefit from further research because much is still unknown about sex differences in DM and CVD. Areas that are discussed include hormonal differences between the sexes and their possible effects on the interaction between DM and CVD, sex differences in epidemiology, ethnic and racial differences and risk factors for CVD in DM across the life span, sex differences in various types of CVD and heart failure, and sex differences in the effects of treatments for DM, including both medications and lifestyle. In addition, there is discussion about risk factors that are specific to women, including gestational diabetes mellitus (GDM) and polycystic ovarian syndrome (PCOS), which affect CVD risk. Table 1 focuses on sex differences in CVD risk factors and outcomes in DM, and Table 2 provides information about sex differences in CVD treatments and interventions in DM. Table 3 contains some of the important ideas for research in sex differences in the cardiovascular consequences of DM. The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on July 31, 2015, and the American Heart Association Executive Committee on September 5, 2015. A copy of the document is available at http://my.americanheart.org/statements by selecting either the "By...

Among young women, measures of free testosterone were independently and inversely associated with BNP and NT-proBNP. These results suggest that circulating free testosterone, not estradiol, mediates gender differences in natriuretic peptides. In addition, the association between higher BMI and lean body mass with natriuretic peptides may be mediated by testosterone.

Following UUO, the co-localization of hypoxia with cellular proliferation, necrosis, and TBM thickening of the PT is consistent with ischemic injury resulting from vasoconstriction. In contrast, a selective dilation of the distal portion of the nephron (DT and CD), which results from the greater tubular compliance there, leads to stretch-induced epithelial cell apoptosis, along with a progressive peritubular fibrosis. Nephron loss in the obstructed developing kidney likely results from complex, segment-specific cellular responses.

Abstract-The role for mitochondrial electron transport chain (ETC) in neurogenic hypertension is unidentified. We evaluated the hypothesis that feedforward depression of mitochondrial ETC functions by superoxide anion (O 2 ⅐Ϫ ) and hydrogen peroxide (H 2 O 2 ) in rostral ventrolateral medulla (RVLM), a brain stem site that maintains sympathetic vasomotor tone and contributes to oxidative stress and neural mechanism of hypertension. Compared with normotensive Wistar-Kyoto rats, spontaneously hypertensive rats exhibited mitochondrial ETC dysfunctions in RVLM in the forms of depressed complex I or III activity and reduced electron coupling capacity between complexes I and III or II and III. Key Words: hypertension Ⅲ free radicals Ⅲ antioxidants Ⅲ reactive oxygen species Ⅲ nervous system Ⅲ sympathetic Ⅲ blood pressure A n imbalance of production over degradation leads to cellular accumulation of reactive oxygen species (ROS), including superoxide anion (O 2 ⅐Ϫ ) and hydrogen peroxide (H 2 O 2 ). The resultant oxidative stress is involved in the pathogenesis of hypertension. 1,2 In the brain, an increase in tissue availability of ROS in the hypothalamus, 3 subfornical regions, 4 or brain stem 3,5,6 contributes to neurogenic hypertension. Thus, the basal level of O 2 ⅐Ϫ and H 2 O 2 in the rostral ventrolateral medulla (RVLM), a brain stem site for the generation and maintenance of sympathetic vasomotor tone, 7 is elevated in animal models of hypertension. 5,6,8 In addition, the expression and activity of the ROS degradative enzymes, particularly superoxide dismutase (SOD) and catalase, are notably reduced 6 in the RVLM of hypertensive animals. Treatment with the SOD mimetic Tempol 9,10 or overexpression of SOD or catalase transgene 6,8 in RVLM, on the other hand, blunts the elevated O 2 ⅐Ϫ and H 2 O 2 in RVLM, leading to reduction in sympathetic vasomotor outflow and vasodepression in hypertensive rats. NADPH oxidase and mitochondria are 2 major sources of ROS in the brain. 11,12 An increase in the generation of NADPH oxidase-derived O 2 ⅐Ϫ in neurons from brain regions involved in cardiovascular control plays a crucial role in the pathogenesis of neurogenic hypertension. 12 At the same time, mitochondrial O 2 ⅐Ϫ is produced in vivo by leakage of electrons from electron transport chain (ETC) complexes during normal cellular respiration. For example, a reduction in complex I enzyme activity leads to accumulation of electrons in the initial part of the transport chain (complex I and coenzyme Q), 13 which facilitates direct transfer of electrons to molecular oxygen that results in the generation of O 2 ⅐Ϫ . A decline in substrate binding activity of complex III, alongside reduced electron coupling capacity for succinate cytochrome c reductase (SCCR) to transport electrons to

Summary:Purpose: Prolonged and continuous epileptic seizure (status epilepticus) results in cellular changes that lead to neuronal damage. We investigated whether these cellular changes entail mitochondrial dysfunction and ultrastructural damage in the hippocampus, by using a kainic acid (KA)-induced experimental status epilepticus model.Methods: In Sprague-Dawley rats maintained under chloral hydrate anesthesia, KA (0.5 nmol) was microinjected unilaterally into the CA3 subfield of the hippocampus to induce seizure-like hippocampal EEG activity. The activity of key mitochondrial respiratory chain enzymes in the dentate gyrus (DG), or CA1 or CA3 subfield of the hippocampus was measured 30 or 180 min after application of KA. Ultrastructure of mitochondria in those three hippocampal subfields during KAinduced status epilepticus also was examined with electron microscopy.Results: Microinjection of KA into the CA3 subfield of the hippocampus elicited progressive build-up of seizure-like hippocampal EEG activity. Enzyme assay revealed significant depression of the activity of nicotinamide adenine dinucleotide cytochrome c reductase (marker for Complexes I+III) in the DG, or CA1 or CA3 subfields 180 min after KA-elicited temporal lobe status epilepticus. Conversely, the activities of succinate cytochrome c reductase (marker for Complexes II+III) and cytochrome c oxidase (marker for Complex IV) remained unaltered. Discernible mitochondrial ultrastructural damage, varying from swelling to disruption of membrane integrity, also was observed in the hippocampus 180 min after hippocampal application of KA.Conclusions: Our results demonstrated that dysfunction of Complex I respiratory chain enzyme and mitochondrial ultrastructural damage in the hippocampus are associated with prolonged seizure during experimental temporal lobe status epilepticus. Key Words: Kainic acid-Status epilepticusHippocampus-Complex I of mitochondrial respiratory chainMitochondrial ultrastructure.Mitochondria are ubiquitous intracellular organelles enclosed by a double membrane-bound structure. The primary function of mitochondria is production of cellular energy in the form of adenosine triphosphate (ATP) by way of oxidative phosphorylation through the mitochondrial respiratory chain. Mitochondrial oxidative phosphorylation consists of five enzyme complexes (Complexes I-V) located in the mitochondrial inner membrane (1). Biochemical evidence suggested that the majority of cerebral ATP consumption is used to operate the electrogenic activity of neurons (2). Adequate energy supply by mitochondria is therefore essential for neuronal excitability and neuronal survival.Seizure activity results in a large number of changes and cascades of cellular events, including gene expression, receptor composition, synaptic physiology, and activation of

The cellular and molecular basis of brain stem death remains an enigma. As the origin of a "life-and-death" signal that reflects the progression toward brain stem death, the rostral ventrolateral medulla (RVLM) is a suitable neural substrate for mechanistic delineation of this phenomenon. Here, we evaluated the hypothesis that heat shock proteins (HSPs) play a neuroprotective role in the RVLM during brain stem death and delineated the underlying mechanisms, using a clinically relevant animal model that employed the organophosphate pesticide mevinphos (Mev) as the experimental insult. In Sprague-Dawley rats, proteomic, Western blot, and real-time PCR analyses demonstrated that Mev induced de novo synthesis of HSP60 or HSP70 in the RVLM without affecting HSP90 level. Loss-of-function manipulations of HSP60 or HSP70 in the RVLM using antiserum or antisense oligonucleotide potentiated Mev-elicited cardiovascular depression alongside reduced nitric-oxide synthase (NOS) I/protein kinase G signaling, enhanced NOS II/peroxynitrite cascade, intensified nucleosomal DNA fragmentation, elevated cytoplasmic histone-associated DNA fragments or activated caspase-3, and augmented the cytochrome c/caspase-3 cascade of apoptotic signaling in the RVLM. Coimmunoprecipitation experiments further revealed a progressive increase in the complex formed between HSP60 and mitochondrial or cytosolic Bax or mitochondrial Bcl-2 during Mev intoxication, alongside a dissociation of the cytosolic HSP60-Bcl-2 complex. We conclude that HSP60 and HSP70 confer neuroprotection against Mev intoxication by ameliorating cardiovascular depression via an anti-apoptotic action in the RVLM. The possible underlying intracellular processes include enhancing NOS I/protein kinase G signaling and inhibiting the NOS II/peroxynitrite cascade. In addition, HSP60 exerts its effects against apoptosis by blunting Mev-induced activation of the Bax/cytochrome c/caspase-3 cascade.Whereas brain stem death is currently the clinical definition of death in many countries (1, 2), the cellular and molecular underpinnings of this phenomenon of paramount medical importance are wanting. The invariable prognosis, that asystole takes place within hours or days after the diagnosis of brain stem death (3), strongly suggests that permanent impairment of the brain stem cardiovascular regulatory machinery should precede death. It is therefore intriguing that our laboratory demonstrated previously that a common denominator exists among patients who succumbed to systemic inflammatory response syndrome (4), severe brain injury (5), or organophosphate poisoning (6). We found that a dramatic reduction or loss of the power density of the low frequency (LF) 3 component (0.04 -0.15 Hz in human) in the systemic arterial pressure (SAP) spectrum, which reflects failure of brain stem cardiovascular regulatory functions, invariably precedes death. We further established that this "life-and-death" signal takes origin from the rostral ventrolateral medulla (RVLM) (7), the brain stem site responsible ...

Summary Purpose:  One cellular consequence of status epilepticus is apoptosis in the hippocampal CA3 subfield. We evaluated the hypothesis that the repertoire of cellular events that underlie such elicited cell death entails mitochondrial dysfunction induced by an excessive production of nitric oxide synthase II (NOS II)‐derived NO, increased superoxide anion (O2−) production, and peroxynitrite formation. Methods:  In Sprague‐Dawley rats, kainic acid was microinjected unilaterally into the hippocampal CA3 subfield to induce bilateral seizure‐like electroencephalography (EEG) activity. The effects of pretreatments with various test agents on the induced O2− production, peroxynitrite formation, mitochondrial respiratory chain enzyme activities, cytochrome c/caspase‐3 signaling, and DNA fragmentation in bilateral CA3 subfields were examined. Results:  Significantly and temporally correlated increase in O2− and peroxynitrite levels (3 to 24 h), depressed mitochondrial Complex I activity (3 h), enhanced translocation of cytochrome c to cytosol (day 1), and augmented activated caspase‐3 (day 7) and DNA fragmentation (day 7) were detected bilaterally in hippocampal CA3 subfields after the elicitation of sustained seizure. Pretreatment with microinjection into the bilateral hippocampal CA3 subfield of a water‐soluble formulation of coenzyme Q10; a selective NOS II inhibitor, S‐methylisothiourea; a superoxide dismutase mimetic, 4‐hydroxy‐2,2,6,6‐tetramethylpiperidine‐1‐oxyl; an active peroxynitrite decomposition catalyst, 5,10, 15,20‐tetrakis‐(N‐methyl‐4‐pyridyl)‐ porphyrinato iron (III); or a peroxynitrite scavenger, L‐cysteine significantly blunted these cellular events. Discussion:  Prolonged seizures prompted NO‐, O2−‐, and peroxynitrite‐dependent reduction in mitochondrial respiratory enzyme Complex I activity, leading to cytochrome c/caspase‐3‐dependent apoptotic cell death in the hippocampal CA3 subfield after induction of experimental temporal lobe status epilepticus.