La patología de granos argirófilos y la taupatía de tipo Alzheimer: características comunes y diferenciales
Author
Rábano, AlbertoAdvisor
Ávila de Grado, JesúsEntity
UAM. Departamento de Biología MolecularDate
2014-02-04Subjects
Proteina tau - Tesis doctorales; Alzheimer, Enfermedad de - Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 04-02-2014Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
Argyrophylic grain disease (AGD) is a sporadic 4R tauopathy that usually presents in combination with
other sporadic tauopathies or with Alzheimer’s disease (AD) pathology, and may contribute to dementia
in older age patients. In previous studies, a detailed analysis of AGD pathology in the medial
temporal lobe has been hampered by the common presence of concurrent Alzheimer’s changes. With
the objective to assess the potentiality of AGD in research on tau pathogenesis and propagation, here
we present a study of a series of AGD postmortem cases (n = 53), selected from a reference series of
511 brains donated to 3 brain banks in Spain. All cases were thoroughly evaluated according to consensus
neuropathological methods and protocols. A detailed neuropathological evaluation of the
medial temporal lobe was accomplished at three coronal levels with Gallyas stain, p62, AT8 and
AT100 antibodies. A subgroup of cases with Braak‐stage ≤ II (n = 23) was selected for detailed morphological
and molecular study. Western blot analysis of the entorhinal and hippocampal cortex was
performed in 8 cases with a panel of anti‐tau antibodies. Cases were genotyped for APOE polymorphism
and for H1/H2 alleles of the MAPT gene. All cases, and particularly lower‐Braak stage cases,
displayed a highly homogeneous pattern of involvement by argyrophylic grains and pretangles between
connected regions (primarily, basolateral nuclei of the amygdala, entorhinal/transentorhinal
cortex, hippocampal cortex). Staging of cases reveals progression of pathology along well‐established
neuroanatomical pathways, with independence of the progression of Alzheimer’s type pathology
(either tau or β‐amyloid pathology). Western blot studies yielded a specific pattern of isoforms with a
characteristic predominant band at 64k. Genetic analysis showed a strong association to the H1 allele
of the MAPT gene. AGD may thus be an optimal natural disease model for testing hypotheses related
to tau propagation in human tissue.
Additionally, the entorhinal cortex of 6 control brains was studied in order to establish the differential
features of the upper layers, where the earliest cell lesions of Alzheimer’s type and argyrophylic grain
pathologies develop. To define the molecular characteristics of these neuron populations, microarrays
were used to define the gene expression in that region. In this way, we identified several genes
that are expressed distinctly in the upper and lower layers of the entorhinal cortex. These include the
genes encoding the matrix Gla protein, collagen type 1_2, reelin, semaphorin 3C or the relaxin receptor,
all related to the extracellular matrix. Thus, differences in the extracellular matrix components
between the upper and lower layers of the entorhinal cortex may in part explain the vulnerability of
neurons present in the upper layers of this brain region in disorders like Alzheimer’s disease or
argyrophylic grain disease.
In a further study here included 5 brains with Alzheimer’s type pathology were studied using intracellular
injections of Lucifer yellow in fixed tissue to analyse over 19500 dendritic spines that were completely
reconstructed in three dimensions along the length of the basal dendrites of pyramidal neurons
in the parahippocampal cortex and CA1. Following intracellular injection, sections were
immunostained for anti‐Lucifer yellow and with tau monoclonal antibodies AT8 and PHF‐1. We observed
that the diffuse accumulation of phospho‐tau in a putative pre‐tangle state did not induce
changes in the dendrites of pyramidal neurons, whereas the presence of tau aggregates forming
intraneuronal neurofibrillary tangles was associated with progressive alteration of dendritic spines
(loss of dendritic spines and changes in their morphology) and dendrite atrophy, depending on the
degree of tangle development.
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