Does Physical Exercise Modify the Pathophysiology of Alzheimer's Disease in Older Persons?

Physical exercise is well known for its benefits on brain health. However, the mechanisms through which these benefits occur remain discussed, especially in the context of cognitive conditions such as Alzheimer's disease. The present short review summarizes the findings of interventional studies that examined the effects of exercise training on the specific and non-specific biomarkers of Alzheimer's disease. Controlled exercise intervention studies published in the English language were selected if they assessed the effects of a physical exercise intervention of at least 2 weeks in middle-aged or older adults on one of the following biomarkers measured either in the brain, the cerebrospinal fluid or the blood: beta-amyloid, tau, neurofilament light chain, and glial fibrillary acidic protein. Overall, there was no strong evidence of significant effects of exercise interventions on any of the selected biomarkers. However, in specific populations, such as women with obesity, pre-diabetes, or depression, favorable changes in blood beta-amyloid concentrations were reported. Further benefits on cerebrospinal fluid beta-amyloid were also demonstrated in APOE-ε4 allele carriers with Alzheimer's disease. In conclusion, the current evidence suggests that physical exercise does not modulate the pathophysiology of Alzheimer's disease in the overall population of middle-aged and older adults. Nonetheless, some specific populations, such as women with metabolic disorders and Alzheimer's disease patients with APOE-ε4 genotype, seem to be favorably affected. Further studies, including long follow-ups, large sample sizes, and concomitantly assessing the effects of other factors such as sedentary behavior and diet, are required to bring further evidence to the field.

Can We Distinguish Age-Related Frailty from Frailty Related to Diseases ? Data from the MAPT Study.

BACKGROUND: No study has tried to distinguish subjects that become frail due to diseases (frailty related to diseases) or in the absence of specific medical events; in this latter case, it is possible that aging process would act as the main frailty driver (age-related frailty). OBJECTIVES: To classify subjects according to the origin of physical frailty: age-related frailty, frailty related to diseases, frailty of uncertain origin, and to compare their clinical characteristics. MATERIALS AND METHODS: We performed a secondary analysis of the Multidomain Alzheimer Preventive Trial (MAPT), including 195 subjects ≥70 years non-frail at baseline who became frail during a 5-year follow-up (mean age 77.8 years ± 4.7; 70% female). Physical frailty was defined as presenting ≥3 of the 5 Fried criteria: weight loss, exhaustion, weakness, slowness, low physical activity. Clinical files were independently reviewed by two different clinicians using a standardized assessment method in order to classify subjects as: "age-related frailty", "frailty related to diseases" or "frailty of uncertain origin". Inconsistencies among the two raters and cases of uncertain frailty were further assessed by two other experienced clinicians. RESULTS: From the 195 included subjects, 82 (42%) were classified as age-related frailty, 53 (27%) as frailty related to diseases, and 60 (31%) as frailty of uncertain origin. Patients who became frail due to diseases did not differ from the others groups in terms of functional, cognitive, psychological status and age at baseline, however they presented a higher burden of comorbidity as measured by the Cumulative Illness Rating Scale (CIRS) (8.20 ± 2.69; vs 6.22 ± 2.02 frailty of uncertain origin; vs. 3.25 ± 1.65 age-related frailty). Time to incident frailty (23.4 months ± 12.1 vs. 39.2 ± 19.3 months) and time spent in a pre-frailty condition (17.1 ± 11.4 vs 26.6 ± 16.6 months) were shorter in the group of frailty related to diseases compared to age-related frailty. Orthopedic diseases (n=14, 26%) were the most common pathologies leading to frailty related to diseases, followed by cardiovascular diseases (n=9, 17%) and neurological diseases (n = 8, 15%). CONCLUSION: People classified as age-related frailty and frailty related to diseases presented different frailty-associated indicators. Future research should target the underlying biological cascades leading to these two frailty classifications, since they could ask for distinct strategies of prevention and management.

Partial characterization of the gene encoding myoadenylate deaminase from the teleost fish Platichthys flesus.

AMP-deaminase (AMPD, EC 3.5.4.6), which catalyzes the irreversible hydrolytic deamination of AMP to IMP and ammonia, is an important energy-related enzyme. The partial genomic sequence of the gene encoding myoadenylate deaminase (AMPD1) from the teleost fish Platichthys flesus was determined. The amino acid sequence of P. flesus AMPD1 shows 82% homology with that of the teleost fish Danio rerio. Comparison of genomic sequences of P. flesus and Rattus norvegicus reveals a high degree of conservation of both sequence and structural organization. A phylogenetic analysis of AMPD sequences shows that bony fish and mammalian AMPD1s arise by duplication of a common primordial gene.

[Knowledge, opinions and tobacco consumption in a French faculty of medicine]. / Connaissances, opinions et consommation de tabac au sein d'une faculté de médecine française.

OBJECTIVE: Tobacco consumption among French physicians is regularly followed-up and well-known; however, there is little information concerning the smoking habits of medical students even though they are the physicians of the future. How do they behave? Do they smoke? More or less than the other populations of the same age? METHOD: All the students of a Parisian medical school were surveyed with a self-questionnaire completed and collected just before the exams at the end of the year. The questionnaire incorporated both past and present smoking habits and also the students' knowledge and opinions on tobacco consumption. RESULTS: A total of 681 students replied. More than one-third were smokers (34.6%) among which 21.0% smoked every day and 13.6% smoked occasionally. Gender had no influence on prevalence rate and both men and women smoked a comparable number of cigarettes per day (males 12.0 cig/day, females 10.4 cig/day). Eleven percent were former smokers and 68.4% would like to quit. Nearly 100% believed that cigarette smoke can bother others and 75% felt they were exemplary figures for others on the subject of tobacco use. Finally, two-thirds of the students smoked light cigarettes. CONCLUSION: The smoking habits of medical students are similar to those of the general population of the same age. It is necessary to develop specific prevention programs for medical students because they will play an important public health role in the future in reducing the prevalence of tobacco consumption in France.

Characterization of two DNA polymerases from the hyperthermophilic euryarchaeon Pyrococcus abyssi.

The complete genome sequence of the hyperthermophilic archaeon Pyrococcus abyssi revealed the presence of a family B DNA polymerase (Pol I) and a family D DNA polymerase (Pol II). To extend our knowledge about euryarchaeal DNA polymerases, we cloned the genes encoding these two enzymes and expressed them in Escherichia coli. The DNA polymerases (Pol I and Pol II) were purified to homogeneity and characterized. Pol I had a molecular mass of approximately 90 kDa, as estimated by SDS/PAGE. The optimum pH and Mg(2+) concentration of Pol I were 8.5-9.0 and 3 mm, respectively. Pol II is composed of two subunits that are encoded by two genes arranged in tandem on the P. abyssi genome. We cloned these genes and purified the Pol II DNA polymerase from an E. coli strain coexpressing the cloned genes. The optimum pH and Mg(2+) concentration of Pol II were 6.5 and 15-20 mm, respectively. Both P. abyssi Pol I and Pol II have associated 3'-->5' exonuclease activity although the exonuclease motifs usually found in DNA polymerases are absent in the archaeal family D DNA polymerase sequences. Sequence analysis has revealed that the small subunit of family D DNA polymerase and the Mre11 nucleases belong to the calcineurin-like phosphoesterase superfamily and that residues involved in catalysis and metal coordination in the Mre11 nuclease three-dimensional structure are strictly conserved in both families. One hypothesis is that the phosphoesterase domain of the small subunit is responsible for the 3'-->5' exonuclease activity of family D DNA polymerase. These results increase our understanding of euryarchaeal DNA polymerases and are of importance to push forward the complete understanding of the DNA replication in P. abyssi.

Purification and characterization of a new DNA polymerase modulator from the hyperthermophilic archaeon Thermococcus fumicolans.

During purification of the native alpha-like DNA polymerase from the hyperthermophilic euryarchaeote Thermococcus fumicolans, two activity peaks were detected after cation-exchange chromatography. One of the peaks (Ppol) was identified as the T. fumicolans DNA polymerase and the second peak (Pf) was shown to contain a factor which increased the DNA polymerase activity over 70-fold when tested with activated calf thymus DNA as substrate. The factor also stimulated nucleotide incorporation when using primed lambda DNA as substrate (approximately 8-fold), while inducing a very large decrease in the turnover rate of the enzyme. The factor, therefore, maximizes the ability of the DNA polymerase to synthesize small fragments, which is compatible with DNA repair or lagging strand DNA replication.

The PCNA from Thermococcus fumicolans functionally interacts with DNA polymerase delta.

We have cloned the gene encoding proliferating cell nuclear antigen (PCNA) from the hyperthermophilic euryarchaeote Thermococcus fumicolans (Tfu). Tfu PCNA contains 250 amino acids with a calculated M(r) of 28,000 and is 26% identical to human PCNA. Next, Tfu PCNA was overexpressed in Escherichia coli and it showed an apparent molecular mass of 33.5 kDa. The purified Tfu PCNA was tested first with recombinant Tfu DNA polymerase I (Tfu pol) and second with calf thymus DNA polymerase delta (pol delta). When tested with the homologous Tfu pol on bacteriophage lambda DNA, large amounts of Tfu PCNA were required to obtain two- to threefold stimulation. Surprisingly, however, Tfu PCNA was much more efficient than human PCNA in stimulating calf thymus pol delta. Our data suggest that PCNA has been functionally conserved not only within eukaryotes but also from hyperthermophilic euryarchaeotes to mammals.

Coordinated changes of adenylate energy charge and ATP/ADP: use in ecotoxicological studies.

The coordinated variations of the adenylate energy charge and ATP/ADP ratio were modeled and a function that depends on the numerical value of the adenylate kinase-catalyzed reaction has been derived. The model allows sensitive detection of the effects of xenobiotics on adenylate kinase and its cellular environment and offers a robust estimation of the direct or indirect effects of pollutants on the adenylate kinase system: data obtained in laboratory studies on shrimp exposed to cadmium and in field studies on oysters either exposed to polychloro-biphenyl compounds or located in a heavily polluted area indicate that xenobiotics affect the adenylate kinase reaction directly or by changing its cellular environment. These results demonstrate that application of the model to the treatment of ecotoxicological data allows detection of energetic changes that would have been missed by simple analysis of the usual energetic parameters, and should overcome problems encountered in using energetic parameters during assessment of pollution monitoring.

Cloning and over-expression in Escherichia coli of the gene encoding NADPH group III alcohol dehydrogenase from Thermococcus hydrothermalis. Characterization and comparison of the native and the recombinant enzymes.

A NADP-dependent group III alcohol dehydrogenase (ADH) was purified from the hyperthermophilic strictly anaerobic archaeon Thermococcus hydrothermalis, which grows at an optimum temperature of 85 degrees C and an optimum pH of 6. The gene encoding this enzyme was cloned, sequenced, and over-expressed in Escherichia coli. The recombinant enzyme was purified, characterized and compared with the native form of the enzyme. The enzyme structure is pH-dependent, being a 197-kDa tetramer (subunit of 45 kDa) at pH 10.5, the pH optimum for alcohol oxidation, and a 80.5-kDa dimer at pH 7.5, the pH optimum for aldehyde reduction. The kinetic parameters of the enzyme show that the affinity of the enzyme is greater for the aldehyde substrate and NADPH cofactor, suggesting that the dimeric form of the enzyme is probably the active form in vivo. The ADH of T. hydrothermalis oxidizes a series of primary aliphatic and aromatic alcohols preferentially from C2 to C8 but is also active towards methanol and glycerol and stereospecific for monoterpenes. T. hydrothermalis ADH is the first Thermococcale ADH to be cloned and overproduced in a mesophilic heterologous expression system, and the recombinant and the native forms have identical main characteristics.

Modelization of coordinated changes of adenylate energy charge and ATP/ADP ratio: application to energy metabolism in invertebrate and vertebrate skeletal muscle.

Regulation of the coordinated adenylate energy charge (AEC) and ATP/ADP ratio variations was studied with the aid of computer-made simulations. When the equilibrium state for the adenylate kinase-catalyzed reaction has been assumed, the function describing the coordinated AEC and ATP/ADP ratio variations can be simply derived from the formulas describing these 2 parameters. The model was used to analyze incidence of AMP deamination in the coordinated regulation of cellular energy metabolism.

Amplification of myoadenylate deaminase during evolution. A comparative study.

Myoadenylate deaminase activity was measured, by using a specific assay technique, in a wide range of animal species, including four invertebrates, one cyclostome, 13 chondrosteans, one teleost and one mammal. The results are discussed considering the known genetic events that have lead to the appearance of the higher vertebrates myoadenylate deaminase molecular form. It is proposed that, during the extensive gene duplication that occurred in the beginning of vertebrate evolution, genetic modification of the myoadenylate deaminase molecule took place in at least two different taxa: the one that evolved to rajiform elasmobranch fishes and the other to the land vertebrates.

Detection of phosphodiester resonances in the perfused heart from vertebrate ectotherms with nuclear magnetic resonance.

In vivo 31P NMR has been used to characterize the phosphorylated compounds present in the heart from vertebrate ectotherms. The perfused hearts from all animals experimented showed prominent resonances between the inorganic phosphate and phosphocreatine peaks. The pattern of these compounds was found to be different in the heart of the different species. As shown by 31P and proton NMR of perchloric extracts, the chemical shift of some of the compounds was characteristic of glycerophosphorylcholine, glycerophosphorylinositol, phosphorylcholine, phosphorylserine, phosphorylethanolamine and phosphoenolpyruvate. The non-identified resonances were found to be phosphodiesters, as demonstrated by alkaline phosphatase hydrolysis. The physiological significance of these high levels of phosphodiesters in the heart from vertebrate ectotherms is discussed.

A specific AMP deaminase assay and its application to tissue homogenates.

1. A rapid method for the determination of AMP and IMP by HPLC is described. 2. Its application to the assay of AMP deaminase allows the specific determination of enzyme activities in crude extracts, eliminating any interference by other enzyme systems (5'-nucleotidase and adenosine deaminase). 3. The method was routinely used for the determination of the AMP deaminase activity in the muscles of marine animals.

Comparative studies on heart and skeletal muscle AMP-deaminase from rainbow trout (Salmo gairdneri).

1. AMP-deaminases from fish heart and skeletal muscle have been isolated, and their kinetic and regulatory properties compared. 2. The results obtained indicate that the enzyme variants present in fish heart and skeletal muscle, in contrast to their mammalian counterparts, show very similar chromatographic, kinetic and regulatory characteristics. 3. The above may reflect evolutionary programmed differences in AMP-deaminase gene(s) organization.

AMP deaminase from equine muscle: purification and determination of regulatory properties.

1. AMP deaminase from thoroughbred horse muscle was purified to apparent homogeneity and its regulatory properties were determined at pH 6.5 and 7.4. 2. The results are discussed in relation to the potential role of muscle AMP deaminase during exercise and the existence of two molecular forms depending on the pH.

In vivo 31P NMR in crustacean muscles: fatigue and recovery in the tail musculature from the prawn Palaemon elegans.

31P NMR has been used to observe the in vivo phosphometabolite concentrations in the tail musculature from the prawn Palaemon elegans, at rest and after escape swimming and subsequent recovery. Muscular fatigue corresponds to a 60% breakdown of phosphoarginine, and a 45% increase of sugar phosphates. The pHi fell from 7.10 to 6.86. During recovery, the sugar phosphates and arginine phosphate are replenished after 20 minutes. The ATP concentration did not change throughout the experiment. The pHi was restored within 20 minutes.

Regulatory properties of pigeon heart muscle AMP deaminase.

The kinetic and regulatory properties of purified pigeon heart muscle AMP deaminase were investigated. In the presence of 100 mM potassium chloride, the enzyme exhibited a slightly sigmoidal type of kinetics. Addition of ATP to the incubation medium changed the reaction rate versus substrate concentration plot into a hyperbolic one, and caused a decrease of the half-saturation constant (S0.5). ADP presence caused the change of both the S0.5 and Vmax parameters, exerting either an activating or inhibitory effect, depending upon the substrate concentration. Orthophosphate inhibited the enzyme at all substrate concentrations, increasing the value of the S0.5 parameter. In the presence of ATP, ADP and orthophosphate, added to the incubation medium at approximately physiological concentrations, pigeon heart AMP deaminase still seems to preserve its activated form. Active long chain fatty acids clearly inhibited enzyme activity even at micromolar concentrations. Interpretation of the kinetic data in terms of the allosteric theory of Monod et al. (1965, J. Mol. Biol. 12, 88-118) indicates that heart muscle AMP deaminase may operate as a functionally active dimer.

Activation of trout gill AMP deaminase by an endogenous proteinase--I. Effects on the regulatory properties of the enzyme.

Some regulatory properties of trout gill AMP deaminase were determined in crude extracts, before or after modification of the enzyme by the endogenous proteinase. After proteolysis, the optimal concentrations for activation by sodium and potassium were shifted from 10 to 75 mM, resulting in a large increase of enzyme activity near the physiological potassium concentration. This activation was shown to be the consequence of a much lower sensitivity of AMP deaminase to inhibition by increasing ionic strength. The modified enzyme was also less sensitive to modifications of pH and to inhibition by physiological concentrations of inorganic phosphate. When all these modifications were considered, limited proteolysis of gill AMP deaminase resulted in a 40 times increase of enzyme activity under in vivo conditions.

Activation of trout gill AMP deaminase by an endogenous proteinase--II. Modification of the properties of the enzyme during starvation, pollution and salinity changes.

The relative amount of modified AMP deaminase has been determined by taking advantage of the different effects of monovalent cations on the two enzymatic forms. When trout were subjected to different environmental perturbations (starvation, pollution of the water by a pesticide, transfer to sea water or reverse transfer to fresh water), modified AMP deaminase could be detected in the gill extracts. Depending on the nature of the stress and the period of experimentation, 8 to 100% of the enzyme had been modified by limited proteolysis. As a consequence of the much higher activity of the proteolyzed AMP deaminase form, a 2 to 12 times increase of the intracellular AMP deaminase activity could be expected. At the same time, limited proteolysis will modify the regulatory properties of the enzyme, since it can be estimated that 50 to 100% of the enzyme activity expressed in the cell will be an AMP deaminase form less sensitive to inhibition by inorganic phosphate and ionic strength, and to variations of the intracellular pH. Limited proteolysis will result in increased AMP deaminase activity under conditions of increased energy demand, where the concentration of inorganic phosphate is dramatically increased. The consequence should be stabilization of the adenylate energy charge.

Activation of trout gill AMP deaminase by an endogenous proteinase--III. Comparative studies on the gill AMP deaminase from different fresh water and sea water teleosts.

The effects of monovalent cations and inorganic phosphate, on gill AMP deaminase, were compared in different fresh water and sea water stenohaline and euryhaline Teleosts. Generally, sea water species displayed a lower sensitivity to these effectors than fresh water species. During salinity changes, the sensitivity of gill AMP deaminase to cations and phosphate were modified proportionally to the tolerance of a given species to variations of environmental salinity. In particular, these parameters were modified in the weak euryhaline, Salmo gairdneri, but not in the real euryhaline, Anguilla anguilla. In sea water adapted trout, the appearance of a modified AMP deaminase form, with similar properties to that found in sea water species, is suggested. When compared with the conclusions from the preceeding papers [Raffin (1986) Comp. Biochem. Physiol. 85B, 157-162; 85B, 163-171], the results suggest that modification of gill AMP deaminase by limited proteolysis should be a rather general adaptation mechanism to stress.