Jordi Olloquequi

Current Research Therapeutic Strategies for Alzheimer’s Disease Treatment

Alzheimers disease (AD) currently presents one of the biggest healthcare issues in the developed countries. There is no effective treatment capable of slowing down disease progression. In recent years the main focus of research on novel pharmacotherapies was based on the amyloidogenic hypothesis of AD, which posits that the beta amyloid (Aβ) peptide is chiefly responsible for cognitive impairment and neuronal death. The goal of such treatments is (a) to reduce Aβ production through the inhibition of β and γ secretase enzymes and (b) to promote dissolution of existing cerebral Aβ plaques. However, this approach has proven to be only modestly effective. Recent studies suggest an alternative strategy centred on the inhibition of the downstream Aβ signalling, particularly at the synapse. Aβ oligomers may cause aberrant N-methyl-D-aspartate receptor (NMDAR) activation postsynaptically by forming complexes with the cell-surface prion protein (PrPC). PrPC is enriched at the neuronal postsynaptic density, where it interacts with Fyn tyrosine kinase. Fyn activation occurs when Aβ is bound to PrPC-Fyn complex. Fyn causes tyrosine phosphorylation of the NR2B subunit of metabotropic glutamate receptor 5 (mGluR5). Fyn kinase blockers masitinib and saracatinib have proven to be efficacious in treating AD symptoms in experimental mouse models of the disease.

Masitinib for the treatment of mild to moderate Alzheimer’s disease

Alzheimer’s disease (AD) is a degenerative neurological disorder that is the most common cause of dementia and disability in older patients. Available treatments are symptomatic in nature and are only sufficient to improve the quality of life of AD patients temporarily. A potential strategy, currently under investigation, is to target cell-signaling pathways associated with neurodegeneration, in order to decrease neuroinflammation, excitotoxicity, and to improve cognitive functions. Current review centers on the role of neuroinflammation and the specific contribution of mast cells to AD pathophysiology. The authors look at masitinib therapy and the evidence presented through preclinical and clinical trials. Dual actions of masitinib as an inhibitor of mast cell–glia axis and a Fyn kinase blocker are discussed in the context of AD pathology. Masitinib is in Phase III clinical trials for the treatment of malignant melanoma, mastocytosis, multiple myeloma, gastrointestinal cancer and pancreatic cancer. It is also in Phase II/III clinical trials for the treatment of multiple sclerosis, rheumatoid arthritis and AD. Additional research is warranted to better investigate the potential effects of masitinib in combination with other drugs employed in AD treatment.

Vulnerability of calbindin, calretinin and parvalbumin in a transgenic/knock-in APPswe/PS1dE9 mouse model of Alzheimer disease together with disruption of hippocampal neurogenesis.

The pathogenesis of Alzheimer disease (AD) is characterized by accumulation of β-amyloid protein in the brain (in both soluble and insoluble forms) and by the presence of intracellular neurofibrillary tangles (NFTs), leading to neurotoxicity. The exact mechanisms whereby Aβ triggers brain alterations are unclear. However, accumulating evidence suggests that a deregulation of Ca(2+) signaling may play a major role in disease progression. Calcium-buffering proteins, including calbindin-D28K (CB), calretinin (CR) and parvalbumin (PV), may offer neuroprotection by maintaining calcium homeostasis. Although marked reductions in these proteins have been observed in the brains of mice and humans with AD, their contribution to AD pathology remains unclear. The aim of the present study was to analyze distribution patterns of CB(+,) CR(+) and PV(+) interneurons in different areas of the hippocampus, a brain region that is severely affected in AD. A transgenic knock-in APPswe/PS1dE9 mouse model of familial AD was used. The data were obtained from the brains of 3- and 12-month-old animals. These ages roughly correspond to an early mature adult (prior to clinical manifestations) and a late middle-age (clinical symptoms readily detectable) phase in human AD patients. Immunostaining revealed increases in CB and PV immunoreactivity (IR) in the hippocampus of 3-month-old transgenic mice, compared to wild-type animals. Possibly, these proteins are upregulated in an attempt to control cellular homeostasis and synaptic plasticity. However, the pattern of CB-IR was reversed in 12-month-old animals, potentially indicating a loss of cellular capacity to respond to pathophysiological processes. In addition, at this age, a noticeable increase in PV-IR was observed, suggesting the presence of hippocampal network hyperactivity in older AD-like mice. Our results indicate that CaBP(+) neuronal subpopulations play a role in adult neurogenesis and in AD pathology, particularly at early disease stages, suggesting that these neurons may serve as potential predictors of future AD in non-demented individuals.

Memantine for the Treatment of Dementia: A Review on its Current and Future Applications

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the presence in the brain of extracellular amyloid-β protein (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. The N-Methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptor, are essential for processes like learning and memory. An excessive activation of NMDARs has been associated with neuronal loss. The discovery of extrasynaptic NMDARs provided a rational and physiological explanation between physiological and excitotoxic actions of glutamate. Memantine (MEM), an antagonist of extrasynaptic NMDAR, is currently used for the treatment of AD jointly with acetylcholinesterase inhibitors. It has been demonstrated that MEM preferentially prevents the excessive continuous extrasynaptic NMDAR disease activation and therefore prevents neuronal cell death induced by excitotoxicity without disrupting physiological synaptic activity. The problem is that MEM has shown no clear positive effects in clinical applications while, in preclinical stages, had very promising results. The data in preclinical studies suggests that MEM has a positive impact on improving AD brain neuropathology, as well as in preventing Aβ production, aggregation, or downstream neurotoxic consequences, in part through the blockade of extrasynaptic NMDAR. Thus, the focus of this review is primarily to discuss the efficacy of MEM in preclinical models of AD, consider possible combinations of this drug with others, and then evaluate possible reasons for its lack of efficacy in clinical trials. Finally, applications in other pathologies are also considered.

Cardiorespiratory Fitness and Muscular Strength as Mediators of the Influence of Fatness on Academic Achievement

OBJECTIVE To examine the combined association of fatness and physical fitness components (cardiorespiratory fitness [CRF] and muscular strength) with academic achievement, and to determine whether CRF and muscular strength are mediators of the association between fatness and academic achievement in a nationally representative sample of adolescents from Chile. STUDY DESIGN Data were obtained for a sample of 36 870 adolescents (mean age, 13.8 years; 55.2% boys) from the Chilean System for the Assessment of Educational Quality test for eighth grade in 2011, 2013, and 2014. Physical fitness tests included CRF (20-m shuttle run) and muscular strength (standing long jump). Weight, height, and waist circumference were assessed, and body mass index and waist circumference-to-height ratio were calculated. Academic achievement in language and mathematics was assessed using standardized tests. The PROCESS script developed by Hayes was used for mediation analysis. RESULTS Compared with unfit and high-fatness adolescents, fit and low-fatness adolescents had significantly higher odds for attaining high academic achievement in language and mathematics. However, in language, unfit and low-fatness adolescents did not have significantly higher odds for obtaining high academic achievement. Those with high fatness had higher academic achievement (both language and mathematics) if they were fit. Linear regression models suggest a partial or full mediation of physical fitness in the association of fatness variables with academic achievement. CONCLUSIONS CRF and muscular strength may attenuate or even counteract the adverse influence of fatness on academic achievement in adolescents.

Dexibuprofen prevents neurodegeneration and cognitive decline in APPswe/PS1dE9 through multiple signaling pathways

The aim of the present study is to elucidate the neuronal pathways associated to NSAIDs causing a reduction of the risk and progression of Alzheimers disease. The research was developed administering the active enantiomer of ibuprofen, dexibuprofen (DXI), in order to reduce associated gastric toxicity. DXI was administered from three to six-month-old female APPswe/PS1dE9 mice as a model of familial Alzheimers disease. DXI treatment reduced the activation of glial cells and the cytokine release involved in the neurodegenerative process, especially TNFα. Moreover, DXI reduced soluble β-amyloid (Aβ1-42) plaque deposition by decreasing APP, BACE1 and facilitating Aβ degradation by enhancing insulin-degrading enzyme. DXI also decreased TAU hyperphosphorylation inhibiting c-Abl/CABLES/p-CDK5 activation signal pathway and prevented spatial learning and memory impairment in transgenic mice. Therefore, chronic DXI treatment could constitute a potential AD-modifying drug, both restoring cognitive functions and reversing multiple brain neuropathological hallmarks.

Health-related physical fitness and weight status in 13- to 15-year-old Latino adolescents. A pooled analysis

OBJECTIVE The aim of this study was to investigate the relation between health-related physical fitness and weight status in 13- to 15-year-old Latino adolescents. METHOD The final sample consisted of 73,561 adolescents aged 13-15 years (35,175 girls) from Chile (n=48,771) and Colombia (n=24,790). Cardiorespiratory and musculoskeletal fitness were measured using 20-m shuttle run (relative peak oxygen uptake - VO2peak) and standing broad jump test (lower body explosive strength), respectively. The International Obesity Task Force definition was used to define weight status (i.e., underweight, normal weight, overweight, and obese). RESULTS The present study found an inverted J-shape relationship between body mass index, cardiorespiratory fitness, and musculoskeletal fitness in both genders and all age groups (p<0.01). Results also suggest that underweight adolescents, and not just overweight and obese adolescents, have lower odds of having a healthy cardiorespiratory fitness (based on new international criterion-referenced standards) profile when compared with their normal weight peers, except in girls aged 14 (p=0.268) and 15 years (p=0.280). CONCLUSIONS The present results indicate low cardiorespiratory fitness and musculoskeletal fitness levels in underweight, overweight, and obese adolescents when compared with their normal weight peers. The findings appear to suggest that exercise programs should to decrease fat mass in overweight/obese adolescents and increase muscle mass in underweight adolescents.

Can physical activity attenuate the negative association between sitting time and cognitive function among older adults? A mediation analysis

&NA; The purpose of this study was to examine the combined association of sitting time and physical activity with cognitive function and to determine whether moderate‐to‐vigorous physical activity (MVPA) is a mediator of the association between sitting time and cognitive function in a nationally representative sample of older adults from Chile. Data from 989 older adults (≥65 years old, 61.3% female) from the 2009–2010 Chilean Health Survey were analyzed. Physical activity and sitting time were measured using the Global Physical Activity questionnaire. Cognitive function was assessed using the modified Mini‐Mental State levels Examination. Physical activity levels were categorized as “inactive” (<600 metabolic equivalent value minutes per week) or “active” (≥600 metabolic equivalent value minutes per week). Sitting time was categorized as “sedentary”, defined as ≥4 h of reported sitting time per day, or “non‐sedentary”, defined as <4 h. We created the following groups (i) non‐sedentary/active; (ii) non‐sedentary/inactive; (iii) sedentary/active; and (iv) sedentary/inactive. Hayess PROCESS macro was used for the simple mediation analysis. Compared with the reference group (individuals classified as non‐sedentary/active), older adults who were classified as sedentary/active had elevated odds of cognitive impairment (OR = 1.90, [95% CI, 1.84 to 3.85]). However, the odds ratio for cognitive impairment was substantially increased in those classified as sedentary/inactive (OR = 4.85 [95% CI, 2.54 to 6.24]) compared with the reference group. MVPA was found to mediate the relationship between sitting time and cognitive function (Indirect Effect = −0.070 [95% CI, −0.012 to −0.004]). Conclusion: The present findings suggest that, whether overall physical activity is high or low, spending large amounts of time sitting is associated with elevated odds of cognitive impairment and that MVPA slightly weakens the relationship between sitting time and cognitive function.

Experimental models for aging and their potential for novel drug discovery.

Background: An interesting area of scientific research is the development of potential antiaging drugs. In order to pursue this goal, it is necessary to gather the specific knowledge about the adequate preclinical models that are available to evaluate the beneficial effects of new potential drugs. This review is focused on invertebrate and vertebrate preclinical models used to evaluate the efficacy of antiaging compounds, with the objective to extend life span and health span. Methods: Research and online content related to aging, antiaging drugs, experimental aging models is reviewed. Moreover, in this review, the main experimental preclinical models of organisms that have contributed to the research in the pharmacol-ogy of lifespan extension and the understanding of the aging process are discussed. Results: Dietary restriction (DR) constitutes a common experimental process to extend life span in all organisms. Besides, classical antiaging drugs such as resveratrol, rapamycin and metformin denominated as DR mimetics are also discussed. Likewise, the main therapeutic targets of these drugs include sirtuins, IGF-1, and mTOR, all of them being modulated by DR. Conclusion: Advances in molecular biology have uncovered the potential molecular pathways involved in the aging process. Due to their characteristics, invertebrate models are mainly used for drug screening. The National Institute on Aging (NIA) developed the Interventions Testing Program (ITP). At the pre-clinical level, the ITP uses Heterogeneous mouse model (HET) which is probably the most suitable rodent model to study potential drugs against aging prevention. The accelerated-senescence mouse P8 is also a mammalian rodent model for aging research. However, when evaluating the effect of drugs on a preclinical level, the evaluation must be done in non-human primates since it is the mammalian specie closest to humans. Research is needed to investigate the impact of new potential drugs for the increase of human quality of