Insoluble Vascular Amyloid Deposits Trigger Disruption of the Neurovascular Unit in Alzheimer’s Disease Brains

Funding: This work was supported by Fondo Nacional de Ciencia y Tecnologia, FONDOCyT, from the Ministry of Higher Education, Science and Technology, Dominican Republic (2015-3A2-127 to MP-H) and (2018-2019-2A3-208 to J.L.-M. and M.P.-H). Acknowledgments: The authors want to express their gratitude to the following: P. Davies†(Albert Einstein College of Medicine, Bronx, NY, USA) and Lester I. Binder† (North Western, Chicago, IL, USA) for the generous gift of mAbs TG-3 and Alz-50, and Tau-1, Tau-5, and Tau-7, respectively; Tec. Amparo Viramontes Pintos for the handling of the brain tissue; support in the confocal microscopy unit of CIIDIR Durango, Instituto Politécnico Nacional; Union Medica University Clinic, Dominican Republic, for their support and collaboration in the development of this research project. We also want to express our gratitude to the Mexican families who have donated the brain of their loved ones affected by Alzheimer’s disease and made our research possible. This work is dedicated to the memory of José Raúl Mena López† . †Deceased.Peer reviewedPublisher PD

Αντιστροφή φύλου του διακοσμητικού ψαριού μονομάχος (Betta splendens, Regan 1910)

<p>C2 phage bound to amyloid aggregates in 50 µm-thick brain tissue sections of temporal cortex from AD patients (A–D) and from cognitively normally aging (NA) elderly subjects (E). Each panel shows, from the left: the reactivity of phage (green); the reactivity of BAM 90.1, an anti-Aβ1–42 monoclonal antibody (red); the merge between red and green channels. A, C and E: scale bar represents 150 µm; B and D: scale bar represents 10 µm.</p

Amyloid-beta Peptide Binds to Cytochrome C Oxidase Subunit 1

Extracellular and intraneuronal accumulation of amyloid-beta aggregates has been demonstrated to be involved in the pathogenesis of Alzheimer's disease (AD). However, the precise mechanism of amyloid-beta neurotoxicity is not completely understood. Previous studies suggest that binding of amyloid-beta to a number of macromolecules has deleterious effects on cellular functions. Mitochondria were found to be the target for amyloid-beta, and mitochondrial dysfunction is well documented in AD. In the present study we have shown for the first time that Aβ 1–42 bound to a peptide comprising the amino-terminal region of cytochrome c oxidase subunit 1. Phage clone, selected after screening of a human brain cDNA library expressed on M13 phage and bearing a 61 amino acid fragment of cytochrome c oxidase subunit 1, bound to Aβ 1–42 in ELISA as well as to Aβ aggregates present in AD brain. Aβ 1–42 and cytochrome c oxidase subunit 1 co-immunoprecipitated from mitochondrial fraction of differentiated human neuroblastoma cells. Likewise, molecular dynamics simulation of the cytochrome c oxidase subunit 1 and the Aβ 1–42 peptide complex resulted in a reliable helix-helix interaction, supporting the experimental results. The interaction between Aβ 1–42 and cytochrome c oxidase subunit 1 may explain, in part, the diminished enzymatic activity of respiratory chain complex IV and subsequent neuronal metabolic dysfunction observed in AD

Peptide mimotopes of Mycobacterium tuberculosis carbohydrate immunodeterminants

Cell-surface saccharides of Mycobacterium tuberculosis appear to be crucial factors in tuberculosis pathogenicity and could be useful antigens in tuberculosis immunodiagnosis. In the present study, we report the successful antigenic and immunogenic mimicry of mannose-containing cell-wall compounds of M. tuberculosis by dodecamer peptides identified by phage-display technology. Using a rabbit antiserum raised against M. tuberculosis cell-surface saccharides as a target for biopanning, peptides with three different consensus sequences were identified. Phage-displayed and chemically synthesized peptides bound to the anticarbohydrate antiserum. Rabbit antibodies elicited against the peptide QEPLMGTVPIRAGGGS recognize the mannosylated M. tuberculosis cell-wall antigens arabinomannan and lipoarabinomannan, and the glycosylated recombinant protein alanine/proline-rich antigen. Furthermore, antibodies were also able to react with mannan from Saccharomyces cerevisiae, but not with phosphatidylinositol dimannosides or arabinogalactan from mycobacteria. These results suggest that the immunogenic peptide mimics oligomannosidic epitopes. Interestingly, this report provides evidence that, in contrast with previously known carbohydrate mimotopes, no aromatic residues are necessary in a peptide sequence for mimicking unusual glycoconjugates synthesized by mycobacteria. The possible usefulness of the identified peptide mimotopes as surrogate reagents for immunodiagnosis and for the study of functional roles of the native non-peptide epitopes is discussed