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Inverse Relationship Between Alzheimer's Disease and Cancer: How Immune Checkpoints Might Explain the Mechanisms Underlying Age-Related Diseases.

2019 , Nicole K. Rogers , Cesar Romero , Carol D. SanMartín , Daniela P. Ponce , Felipe Salech , Mercedes N. López , Alejandra Gleisner , Fabián Tempio , BEHRENS PELLEGRINO, MARIA ISABEL

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Visual-spatial processing impairment in the occipital-frontal connectivity network at early stages of Alzheimer’s disease

2023 , Iván Plaza-Rosales , Enzo Brunetti , Rodrigo Montefusco-Siegmund , Samuel Madariaga , Rodrigo Hafelin , Daniela P. Ponce , BEHRENS PELLEGRINO, MARIA ISABEL , Pedro E. Maldonado , Andrea Paula-Lima

IntroductionAlzheimer’s disease (AD) is the leading cause of dementia worldwide, but its pathophysiological phenomena are not fully elucidated. Many neurophysiological markers have been suggested to identify early cognitive impairments of AD. However, the diagnosis of this disease remains a challenge for specialists. In the present cross-sectional study, our objective was to evaluate the manifestations and mechanisms underlying visual-spatial deficits at the early stages of AD.MethodsWe combined behavioral, electroencephalography (EEG), and eye movement recordings during the performance of a spatial navigation task (a virtual version of the Morris Water Maze adapted to humans). Participants (69–88 years old) with amnesic mild cognitive impairment–Clinical Dementia Rating scale (aMCI–CDR 0.5) were selected as probable early AD (eAD) by a neurologist specialized in dementia. All patients included in this study were evaluated at the CDR 0.5 stage but progressed to probable AD during clinical follow-up. An equal number of matching healthy controls (HCs) were evaluated while performing the navigation task. Data were collected at the Department of Neurology of the Clinical Hospital of the Universidad de Chile and the Department of Neuroscience of the Faculty of Universidad de Chile.ResultsParticipants with aMCI preceding AD (eAD) showed impaired spatial learning and their visual exploration differed from the control group. eAD group did not clearly prefer regions of interest that could guide solving the task, while controls did. The eAD group showed decreased visual occipital evoked potentials associated with eye fixations, recorded at occipital electrodes. They also showed an alteration of the spatial spread of activity to parietal and frontal regions at the end of the task. The control group presented marked occipital activity in the beta band (15–20 Hz) at early visual processing time. The eAD group showed a reduction in beta band functional connectivity in the prefrontal cortices reflecting poor planning of navigation strategies.DiscussionWe found that EEG signals combined with visual-spatial navigation analysis, yielded early and specific features that may underlie the basis for understanding the loss of functional connectivity in AD. Still, our results are clinically promising for early diagnosis required to improve quality of life and decrease healthcare costs.

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Cancer History Is Associated with Slower Speed of Cognitive Decline in Patients with Amnestic Cognitive Impairment

2022 , Rolando I. Castillo-Passi , Rodrigo C. Vergara , Nicole K. Rogers , Daniela P. Ponce , Magdalena Bennett , BEHRENS PELLEGRINO, MARIA ISABEL

Background: Several epidemiological studies report a negative association between Cancer and Alzheimer’s disease (AD). Objective: To characterize the trajectories of memory loss in individuals with early amnestic cognitive impairment with and without history of previous cancer. Methods: Cognitive deterioration was assessed using the Montreal Cognitive Assessment (MoCA) or MoCA-Memory Index Score (MoCA-MIS) biannually in subjects with early amnestic cognitive impairment followed-up retrospectively from 2007 to 2021. History of Cancer was obtained from clinical records. Simple linear regressions of MoCA-MIS scores were calculated for each subject and analyzed with K-means cluster analysis to identify subgroups with different cognitive decline trajectories. χ2 and t tests were used for descriptive categorical and continuous variables and mixed multiple linear regressions to determine cognitive decline covariates. Results: Analysis of the trajectory of cognitive decline in 141 subjects with early amnestic cognitive impairment identified two subgroups: Fast (n = 60) and Slow (n = 81) progressors. At baseline Fast progressors had better MoCA-MIS (p < 0.001) and functionality (CDR p = 0.02, AD8 p = 0.05), took less anti-dementia medications (p = 0.005), and had higher depression rates (p = 0.02). Interestingly, Fast progressors slowed their speed of memory decline (from 1.6 to 1.1 MoCA-MIS points/year) and global cognitive decline (from 2.0 to 1.4 total MoCA points/year) when Cancer history was present. Conclusion: Two trajectories of amnestic cognitive decline were identified, possibly derived from different neurophysiopathologies or clinical stages. This study suggests that a history of previous Cancer slows down amnestic cognitive decline, specifically in a subgroup of subjects with depression at baseline and accelerated deterioration at follow-up.

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Neuronal Rubicon Represses Extracellular APP/Amyloid β Deposition in Alzheimer’s Disease

2022 , Sandra Espinoza , Felipe Grunenwald , Wileidy Gomez , Felipe García , Lorena Abarzúa-Catalan , Sebastián Oyarce-Pezoa , Maria Fernanda Hernandez , Bastián I. Cortés , Markus Uhrig , Daniela P. Ponce , Claudia Durán-Aniotz , Claudio Hetz , Carol D. SanMartín , Victor H. Cornejo , EZQUER, EDUARDO FERNANDO , Valentina Parra , BEHRENS PELLEGRINO, MARIA ISABEL , Patricio A. Manque , Diego Rojas-Rivera , René L. Vidal , Ute Woehlbier , Melissa Nassif

Alzheimer’s disease (AD) is the most prevalent age-associated neurodegenerative disease. A decrease in autophagy during aging contributes to brain disorders by accumulating potentially toxic substrates in neurons. Rubicon is a well-established inhibitor of autophagy in all cells. However, Rubicon participates in different pathways depending on cell type, and little information is currently available on neuronal Rubicon’s role in the AD context. Here, we investigated the cell-specific expression of Rubicon in postmortem brain samples from AD patients and 5xFAD mice and its impact on amyloid β burden in vivo and neuroblastoma cells. Further, we assessed Rubicon levels in human-induced pluripotent stem cells (hiPSCs), derived from early-to-moderate AD and in postmortem samples from severe AD patients. We found increased Rubicon levels in AD-hiPSCs and postmortem samples and a notable Rubicon localization in neurons. In AD transgenic mice lacking Rubicon, we observed intensified amyloid β burden in the hippocampus and decreased Pacer and p62 levels. In APP-expressing neuroblastoma cells, increased APP/amyloid β secretion in the medium was found when Rubicon was absent, which was not observed in cells depleted of Atg5, essential for autophagy, or Rab27a, required for exosome secretion. Our results propose an uncharacterized role of Rubicon on APP/amyloid β homeostasis, in which neuronal Rubicon is a repressor of APP/amyloid β secretion, defining a new way to target AD and other similar diseases therapeutically.

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Vitamin D Increases Aβ140 Plasma Levels and Protects Lymphocytes from Oxidative Death in Mild Cognitive Impairment Patients

2018 , Carol D. SanMartín , Mauricio Henriquez , Carlos Chacon , Daniela P. Ponce , Felipe Salech , Nicole K. Rogers , BEHRENS PELLEGRINO, MARIA ISABEL

Background: Mild cognitive impairment (MCI) has an increased rate of progression to dementia. Alterations of some metabolic factors, such as deficiency of vitamin D, are a risk factor for cognitive deterioration. Vitamin D is involved in the clearance of β-amyloid (Aβ) from the brain. We have reported that lymphocytes from Alzheimer's disease (AD) patients have an increased susceptibility to oxidative death by H2O2 exposure, but currently it is unknown if this characteristic is modifiable in vivo. Objective: To determine if correction of low vitamin D levels protects lymphocytes from oxidative death and increases Aβ1-40 plasma levels in MCI and very early AD (VEAD) patients. Method: Sixteen MCI, 11 VEAD and 25 healthy control (HC) voluntaries were evaluated with the Clinical Dementia Rating (CDR), Montreal Cognitive assessment (MoCA), and Memory Index score (MIS). Lymphocyte death was measured by flow cytometry after 20h exposure to H2O2. In patients with low levels of vitamin D -11 MCI, 9 VEAD and 20 HC- lymphocyte H2O2-death, plasma Aβ1-40 levels and cognitive status were evaluated pre- and post-vitamin D supplementation for 6 months. Results: Lymphocytes from MCI and VEAD patients showed increased susceptibility to oxidative death at study entry. In MCI, but not VEAD patients, lymphocyte susceptibility to death and Aβ1-40 levels plasma levels improved after 6 months of vitamin D supplementation. In addition, cognitive status on follow-up (18 months) improved in MCI patients after vitamin D supplementation. Conclusion: Vitamin D supplementation may be beneficial in MCI. The lack of effect in VEAD may be due to a more advanced stage or different characteristics of the neurodegenerative process.

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Nicotinamide, a Poly [ADP-Ribose] Polymerase 1 (PARP-1) Inhibitor, as an Adjunctive Therapy for the Treatment of Alzheimer’s Disease

2020 , Felipe Salech , Daniela P. Ponce , Andrea C. Paula-Lima , Carol D. SanMartin , BEHRENS PELLEGRINO, MARIA ISABEL

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Senescence Markers in Peripheral Blood Mononuclear Cells in Amnestic Mild Cognitive Impairment and Alzheimer’s Disease

2022 , Felipe Salech , Carol D. SanMartín , Jorge Concha-Cerda , Esteban Romero-Hernández , Daniela P. Ponce , Gianella Liabeuf , Nicole K. Rogers , Paola Murgas , Bárbara Bruna , Jamileth More , BEHRENS PELLEGRINO, MARIA ISABEL

Recent studies suggest that cellular senescence plays a role in Alzheimer’s Disease (AD) pathogenesis. We hypothesize that cellular senescence markers might be tracked in the peripheral tissues of AD patients. Senescence hallmarks, including altered metabolism, cell-cycle arrest, DNA damage response (DDR) and senescence secretory associated phenotype (SASP), were measured in peripheral blood mononuclear cells (PBMCs) of healthy controls (HC), amnestic mild cognitive impairment (aMCI) and AD patients. Senescence-associated βeta-galactosidase (SA-β-Gal) activity, G0-G1 phase cell-cycle arrest, p16 and p53 were analyzed by flow cytometry, while IL-6 and IL-8 mRNA were analyzed by qPCR, and phosphorylated H2A histone family member X (γH2AX) was analyzed by immunofluorescence. Senescent cells in the brain tissue were determined with lipofuscin staining. An increase in the number of senescent cells was observed in the frontal cortex and hippocampus of advanced AD patients. PBMCs of aMCI patients, but not in AD, showed increased SA-β-Gal compared with HCs. aMCI PBMCs also had increased IL-6 and IL8 mRNA expression and number of cells arrested at G0-G1, which were absent in AD. Instead, AD PBMCs had significantly increased p16 and p53 expression and decreased γH2Ax activity compared with HC. This study reports that several markers of cellular senescence can be measured in PBMCs of aMCI and AD patients.

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Analyzing Olfactory Neuron Precursors Non-Invasively Isolated through NADH FLIM as a Potential Tool to Study Oxidative Stress in Alzheimer’s Disease

2021 , Laura Gómez-Virgilio , Alejandro Luarte , Daniela P. Ponce , Bárbara A. Bruna , BEHRENS PELLEGRINO, MARIA ISABEL

Among all the proposed pathogenic mechanisms to understand the etiology of Alzheimer’s disease (AD), increased oxidative stress seems to be a robust and early disease feature where many of those hypotheses converge. However, despite the significant lines of evidence accumulated, an effective diagnosis and treatment of AD are not yet available. This limitation might be partially explained by the use of cellular and animal models that recapitulate partial aspects of the disease and do not account for the particular biology of patients. As such, cultures of patient-derived cells of peripheral origin may provide a convenient solution for this problem. Peripheral cells of neuronal lineage such as olfactory neuronal precursors (ONPs) can be easily cultured through non-invasive isolation, reproducing AD-related oxidative stress. Interestingly, the autofluorescence of key metabolic cofactors such as reduced nicotinamide adenine dinucleotide (NADH) can be highly correlated with the oxidative state and antioxidant capacity of cells in a non-destructive and label-free manner. In particular, imaging NADH through fluorescence lifetime imaging microscopy (FLIM) has greatly improved the sensitivity in detecting oxidative shifts with minimal intervention to cell physiology. Here, we discuss the translational potential of analyzing patient-derived ONPs non-invasively isolated through NADH FLIM to reveal AD-related oxidative stress. We believe this approach may potentially accelerate the discovery of effective antioxidant therapies and contribute to early diagnosis and personalized monitoring of this devastating disease.