Oral biopsies in a Portuguese population: A 20-year clinicopathological study in a university clinic.

Background: Performing a biopsy is very important in oral medicine and the anatomopathological examination is fundamental to obtain or to confirm the diagnosis in oral and maxillofacial pathology. The purpose of this study is to analyse the frequency and characteristic patterns of biopsied oromaxillofacial lesions in a Portuguese population. Material and Methods: A descriptive statistical analysis of the data from the anatomopathological reports of the biopsies performed between 1999 and 2019 at the university clinic of the Faculty of Dental Medicine of the University of Lisbon was performed, regarding the patient's gender and age, type of biopsy, location of lesions, clinical and histological diagnosis, and the results were obtained. Association relationships were studied using the chi-square test and the Kruskal-Wallis test to correlate variables. P<0.05 was considered statistically significant. Results: From a total sample of 1448 patients, 826 (57.1%) were female, 610 (42.1%) were male, and 12 (0.8%) had no gender information, with a mean age of 50.14 years (standard deviation ± 17.61). The preferred location was the buccal mucosa, vestibule fundus and alveolar mucosa (20.7%). Benign lesions (BL) were the most common, in 82,8% of the cases, followed by oral potentially malignant disorders (OPMD) in 15,5%, and finally, malignant lesions (ML) in 1.7%. Focal fibrous hyperplasia was the most frequent diagnosis in the total sample (25.6%). In the young group, the most common entity was mucocele (34.0%), with a predominance of the lower lip (32.9%). In OPMD, leukoplakia was the most frequently diagnosed (48,7%). The most common ML was squamous cell carcinoma (92.0%), appearing mainly in the tongue (34.8%). A statistically significant relation between ML and older age was found. Conclusions: This study included biopsies analysed over a period of 20 years, being BL the main pathology to affect the oral cavity. Although less frequent, OPMD and ML should not be neglected and must be correctly diagnosed and treated. Key words:Oral biopsies, Oral and maxillofacial pathology, Oral medicine, Clinicopathological analysis, Epidemiological study, University clinic.

Internalized antibodies to the Abeta domain of APP reduce neuronal Abeta and protect against synaptic alterations.

Immunotherapy against beta-amyloid peptide (Abeta) is a leading therapeutic direction for Alzheimer disease (AD). Experimental studies in transgenic mouse models of AD have demonstrated that Abeta immunization reduces Abeta plaque pathology and improves cognitive function. However, the biological mechanisms by which Abeta antibodies reduce amyloid accumulation in the brain remain unclear. We provide evidence that treatment of AD mutant neuroblastoma cells or primary neurons with Abeta antibodies decreases levels of intracellular Abeta. Antibody-mediated reduction in cellular Abeta appears to require that the antibody binds to the extracellular Abeta domain of the amyloid precursor protein (APP) and be internalized. In addition, treatment with Abeta antibodies protects against synaptic alterations that occur in APP mutant neurons.

The Arctic Alzheimer mutation favors intracellular amyloid-beta production by making amyloid precursor protein less available to alpha-secretase.

Mutations within the amyloid-beta (Abeta) domain of the amyloid precursor protein (APP) typically generate hemorrhagic strokes and vascular amyloid angiopathy. In contrast, the Arctic mutation (APP E693G) results in Alzheimer's disease. Little is known about the pathologic mechanisms that result from the Arctic mutation, although increased formation of Abeta protofibrils in vitro and intraneuronal Abeta aggregates in vivo suggest that early steps in the amyloidogenic pathway are facilitated. Here we show that the Arctic mutation favors proamyloidogenic APP processing by increased beta-secretase cleavage, as demonstrated by altered levels of N- and C-terminal APP fragments. Although the Arctic mutation is located close to the alpha-secretase site, APP harboring the Arctic mutation is not an inferior substrate to a disintegrin and metalloprotease-10, a major alpha-secretase. Instead, the localization of Arctic APP is altered, with reduced levels at the cell surface making Arctic APP less available for alpha-secretase cleavage. As a result, the extent and subcellular location of Abeta formation is changed, as revealed by increased Abeta levels, especially at intracellular locations. Our findings suggest that the unique clinical symptomatology and neuropathology associated with the Arctic mutation, but not with other intra-Abeta mutations, could relate to altered APP processing with increased steady-state levels of Arctic Abeta, particularly at intracellular locations.

Beta-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system.

Increasing evidence links intraneuronal beta-amyloid (Abeta42) accumulation with the pathogenesis of Alzheimer's disease (AD). In Abeta precursor protein (APP) mutant transgenic mice and in human AD brain, progressive intraneuronal accumulation of Abeta42 occurs especially in multivesicular bodies (MVBs). We hypothesized that this impairs the MVB sorting pathway. We used the trafficking of the epidermal growth factor receptor (EGFR) and TrkB receptor to investigate the MVB sorting pathway in cultured neurons. We report that, during EGF stimulation, APP mutant neurons demonstrated impaired inactivation, degradation, and ubiquitination of EGFR. EGFR degradation is dependent on translocation from MVB outer to inner membranes, which is regulated by the ubiquitin-proteasome system (UPS). We provide evidence that Abeta accumulation in APP mutant neurons inhibits the activities of the proteasome and deubiquitinating enzymes. These data suggest a mechanism whereby Abeta accumulation in neurons impairs the MVB sorting pathway via the UPS in AD.

Adenosine promotes neuronal recovery from reactive oxygen species induced lesion in rat hippocampal slices.

Reactive oxygen species (ROS) are believed to be involved in the pathogenesis of several neurological disorders. We now tested whether the endogenous neuroprotective substance, adenosine, attenuates the cell damage induced by ROS. In rat hippocampal slices, the xanthine oxidase (40 mU/ml) plus xanthine (1 mM) (X/XO) system produced a 27.8+/-7.3% (n=3) increase in ROS, measured by fluorimetry with 2',7'-dichlorodihydrofluorescein, a 246.9+/-18.4% (n=6) increase in the release of tritiated adenosine, and a decrease in synaptic transmission that fully recovered after washout. In the presence of the adenosine A(1) receptor selective antagonist, 1,3-dipropyl-8-cyclopentylxanthine (100 nM), X/XO induced a similar inhibition, however synaptic transmission only recovered to 70.7+/-5.8% of control (n=5). The blockade of A(2A) receptors was devoid of effect (n=4). Adenosine is released by ROS-generating systems, and attenuates the deleterious cellular consequences of ROS through A(1) receptor activation.