Angel Cedazo-Minguez

Defeating Alzheimer's disease and other dementias: a priority for European science and society

Defeating Alzheimers disease and other dementias : a priority for European science and society

DJ-1 acts in parallel to the PINK1/parkin pathway to control mitochondrial function and autophagy

Mutations in DJ-1, PINK1 (PTEN-induced putative kinase 1) and parkin all cause recessive parkinsonism in humans, but the relationships between these genes are not clearly defined. One event associated with loss of any of these genes is altered mitochondrial function. Recent evidence suggests that turnover of damaged mitochondria by autophagy might be central to the process of recessive parkinsonism. Here, we show that loss of DJ-1 leads to loss of mitochondrial polarization, fragmentation of mitochondria and accumulation of markers of autophagy (LC3 punctae and lipidation) around mitochondria in human dopaminergic cells. These effects are due to endogenous oxidative stress, as antioxidants will reverse all of them. Similar to PINK1 and parkin, DJ-1 also limits mitochondrial fragmentation in response to the mitochondrial toxin rotenone. Furthermore, overexpressed parkin will protect against loss of DJ-1 and, although DJ-1 does not alter PINK1 mitochondrial phenotypes, DJ-1 is still active against rotenone-induced damage in the absence of PINK1. None of the three proteins complex together using size exclusion chromatography. These data suggest that DJ-1 works in parallel to the PINK1/parkin pathway to maintain mitochondrial function in the presence of an oxidative environment.

Oxysterols and neurodegenerative diseases.

In contrast to their parent molecule cholesterol, two of its side-chain oxidized metabolites are able to cross the blood-brain barrier. There is a concentration-driven flux of 24S-hydroxycholesterol (24S-OHC) from the brain into the circulation, which is of major importance for elimination of excess cholesterol from the brain. The opposite flux of 27-hydroxycholesterol (27-OHC) from the circulation into the brain may regulate a number of key enzymes within the brain. In vitro experiments suggest that the balance between the levels of these two molecules may be of importance for the generation of beta-amyloid peptides. In primary cultures of rat hippocampal cells 27-OHC is able to suppress expression of the activity regulated cytoskeleton-associated protein (Arc), a protein important in memory consolidation which is reduced in patients with Alzheimers disease (AD). In the present work we explore the possibility that the flux of 27-OHC from the circulation into the brain represents the missing link between AD and hypercholesterolemia, and discuss the possibility that modification of this flux may be a therapeutic strategy. Lastly, we discuss the use of oxysterols as diagnostic markers in neurodegenerative disease.

Mitochondrial Alterations in PINK1 Deficient Cells Are Influenced by Calcineurin-Dependent Dephosphorylation of Dynamin-Related Protein 1

PTEN-induced novel kinase 1 (PINK1) mutations are associated with autosomal recessive parkinsonism. Previous studies have shown that PINK1 influences both mitochondrial function and morphology although it is not clearly established which of these are primary events and which are secondary. Here, we describe a novel mechanism linking mitochondrial dysfunction and alterations in mitochondrial morphology related to PINK1. Cell lines were generated by stably transducing human dopaminergic M17 cells with lentiviral constructs that increased or knocked down PINK1. As in previous studies, PINK1 deficient cells have lower mitochondrial membrane potential and are more sensitive to the toxic effects of mitochondrial complex I inhibitors. We also show that wild-type PINK1, but not recessive mutant or kinase dead versions, protects against rotenone-induced mitochondrial fragmentation whereas PINK1 deficient cells show lower mitochondrial connectivity. Expression of dynamin-related protein 1 (Drp1) exaggerates PINK1 deficiency phenotypes and Drp1 RNAi rescues them. We also show that Drp1 is dephosphorylated in PINK1 deficient cells due to activation of the calcium-dependent phosphatase calcineurin. Accordingly, the calcineurin inhibitor FK506 blocks both Drp1 dephosphorylation and loss of mitochondrial integrity in PINK1 deficient cells but does not fully rescue mitochondrial membrane potential. We propose that alterations in mitochondrial connectivity in this system are secondary to functional effects on mitochondrial membrane potential.

Apolipoprotein E ɛ4 magnifies lifestyle risks for dementia: a population‐based study

The risk of dementia and Alzheimers disease (AD) probably results from an interaction between genetic and environmental factors. The aim of this study was to investigate the effects and putative interactions between the apoE ɛ4 allele and lifestyle related risk factors for dementia and AD. Participants of the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study were derived from random, population‐based samples previously studied in 1972, 1977, 1982 or 1987. After an average follow‐up of 21 years, 1449 individuals (72.5%) aged 65–79 years were re‐examined in 1998. The apoE ɛ4 allele was an independent risk factor for dementia/AD even after adjustments for sociodemographic, lifestyle and vascular factors (odds ratio [OR]= 2.83, 95% confidence interval [CI]ɛ1.61–4.97). Physical inactivity, alcohol drinking and smoking increased the risk of dementia/AD particularly among the apoE ɛ4 carriers. Furthermore, low–moderate intake of polyunsaturated, and moderate–high intake of saturated fats were associated with an increased risk of dementia/AD more pronouncedly among apoE ɛ4 carriers. Composite effect of the lifestyle factors was particularly seen among the ɛ4 carriers (OR = 11.42, 95% CI = 1.94–67.07 in the 4th quartile). Physical inactivity, dietary fat intake, alcohol drinking and smoking at midlife are associated with the risk of dementia and AD, especially among the apoE ɛ4 carriers. The apoE ɛ4 carriers may be more vulnerable to environmental factors, and thus, lifestyle interventions may greatly modify dementia risk particularly among the genetically susceptible individuals.

Apolipoprotein E and Alzheimer's disease: molecular mechanisms and therapeutic opportunities.

•  Introduction •  ApoE function •  ApoE role in AD pathology –  ApoE and Aβ –  ApoE and neurofibrillary tangles –  ApoE, cholesterol and synaptic repair –  ApoE and cholinergic dysfunction –  ApoE and signalling –  ApoE and neurotoxicity •  ApoE as a therapeutic target for AD •  Conclusions

Involvement of glutaredoxin-1 and thioredoxin-1 in β-amyloid toxicity and Alzheimer's disease

Strong evidence indicates oxidative stress in the pathogenesis of Alzheimers disease (AD). Amyloid β (Aβ) has been implicated in both oxidative stress mechanisms and in neuronal apoptosis. Glutaredoxin-1 (GRX1) and thioredoxin-1 (TRX1) are antioxidants that can inhibit apoptosis signal-regulating kinase (ASK1). We examined levels of GRX1 and TRX1 in AD brain as well as their effects on Aβ neurotoxicity. We show an increase in GRX1 and a decrease in neuronal TRX1 in AD brains. Using SH-SY5Y cells, we demonstrate that Aβ causes an oxidation of both GRX1 and TRX1, and nuclear export of Daxx, a protein downstream of ASK1. Aβ toxicity was inhibited by insulin-like growth factor-I (IGF-I) and by overexpressing GRX1 or TRX1. Thus, Aβ neurotoxicity might be mediated by oxidation of GRX1 or TRX1 and subsequent activation of the ASK1 cascade. Deregulation of GRX1 and TRX1 antioxidant systems could be important events in AD pathogenesis.

Apolipoprotein E: a major piece in the Alzheimer's disease puzzle.

Alzheimers disease (AD) is a complex neurodegenerative disorder with multiple etiologies. The presence of the E4 isoform of apolipoprotein E (apoE) has been shown to increase the risk and to decrease the age of onset for AD and is the major susceptibility factor known for the disease. ApoE4 has been shown to intensify all the biochemical distrubances characteristic of AD, including beta amyloid (Aβ) deposition, tangle formation, neuronal cell death, oxidative stress, synaptic plasticity and dysfunctions of lipid homeostasis and cholinergic signalling. In contrast, other apoE isoforms are protective. Here we review and discuss these major hypotheses of the apoE4‐AD association.

Pathways to Alzheimer's disease

Recent trials of anti‐amyloid agents have not produced convincing improvements in clinical outcome in Alzheimers disease; however, the reason for these poor or inconclusive results remains unclear. Recent genetic data continue to support the amyloid hypothesis of Alzheimers disease with protective variants being found in the amyloid gene and both common low‐risk and rare high‐risk variants for disease being discovered in genes that are part of the amyloid response pathways. These data support the view that genetic variability in how the brain responds to amyloid deposition is a potential therapeutic target for the disease, and are consistent with the notion that anti‐amyloid therapies should be initiated early in the disease process.

Biomarkers for Alzheimer's disease and other forms of dementia: Clinical needs, limitations and future aspects

An early diagnosis of Alzheimers disease (AD) and other types of dementia-causing disorders is vital in order to achieve effective treatments. Fortunately, in the recent years the search for specific biomarkers has undergone a rapid evolution. New technologies in proteomics and genomics have permitted great advances in defining biochemical markers in cerebrospinal fluid (CSF) and in blood. Novel imaging techniques are also improving the diagnosis and early detection of brain changes in vivo. Furthermore, combined analysis of different biomolecules, or of biochemical and neuroimaging studies, increase diagnostic sensitivity and specificity. However, the discovery of sensitive and specific biomarkers for neurodegenerative diseases needs to overcome some important challenges. With the available technology, standardization of methods is essential to reducing inconsistency and increasing reliability. Global initiatives, multicenter studies and consensus protocols of analysis are of critical importance. The present review summarizes the results achieved in the search for an early diagnosis of neurodegenerative disorders, and reflects the limitations and the perspectives of the field.