Journal of Alzheimer's Disease - Volume 7, issue 3 - Journals

Alzheimer's disease and models of computation: Imaging, classification, and neural models

Authors: Adeli, Hojjat | Ghosh-Dastidar, Samanwoy | Dadmehr, Nahid

Article Type: Research Article

Abstract: Prediction or early-stage diagnosis of Alzheimer's disease (AD) requires a comprehensive understanding of the underlying mechanisms of the disease and its progression. Researchers in this area have approached the problem from multiple directions by attempting to develop (a) neurological (neurobiological and neurochemical) models, (b) analytical models for anatomical and functional brain images, (c) analytical feature extraction models for electroencephalograms (EEGs), (d) classification models for positive identification of AD, and (e) neural models of memory and memory impairment in AD. This article presents a state-of-the-art review of research performed on computational modeling of AD and its markers. The review covers the …following approaches: computer imaging, classification models, connectionist neural models, and biophysical neural models. It is concluded that a mixture of markers and a combination of novel computational techniques such as neural computing, chaos theory, and wavelets can increase the accuracy of algorithms for automated detection and diagnosis of AD. Show more

Keywords: Alzheimer's disease, EEG, imaging, biophysical, connectionist, neural models

DOI: 10.3233/JAD-2005-7301

Citation: Journal of Alzheimer's Disease, vol. 7, no. 3, pp. 187-199, 2005

Price: EUR 27.50

Sodium azide and 2-deoxy-D-glucose-induced cellular stress affects phosphorylation-dependent AβPP processing

Authors: Henriques, Ana Gabriela | Domingues, Sara C.T.S. | Fardilha, Margarida | da Cruz e Silva, Edgar F. | da Cruz e Silva, Odete A.B.

Article Type: Research Article

Abstract: Production of the amyloid β (Aβ) peptide via altered metabolism of the amyloid β-Protein Precursor (AβPP) appears to be a key event in the pathology of Alzheimer Disease (AD). Accordingly, altered processing of AβPP was observed under conditions of abnormal cellular stress induced by sodium azide in the presence of 2-deoxy-D-glucose (2DG). As previously reported, the production of sAβPP (the secreted fragment of AβPP) was inhibited. However, our data further suggests that 2DG alone can account for most of the observed effects on AβPP processing in COS-1 cells and PC12 cells. It appears that 2DG interferes with the normal glycosylation …of AβPP and its maturation process, having direct consequences on sAβPP production. Interestingly, PMA (phorbol 12-myristate 13-acetate)-induced sAβPP production was maintained under the stress conditions used, suggesting that potential non-amyloidogenic AβPP processing can still be favoured. This is of potential therapeutic interest, since it indicates that even under adverse stress conditions drugs such as PMA can affect AβPP processing, leading to increased sAβPP production and a concomitant reduction in Aβ production. However, the induction of sAβPP production was not identical when the phosphatase inhibitor OA (okadaic acid) was used. In fact, the typical OA-induced increase in sAβPP production could be abolished under specific conditions. This constitutes an interesting precedent for the possible dissociation of the PMA and OA responses in terms of sAβPP production. The involvement of protein phosphatases, which are inhibited by OA, in AβPP processing, was reinforced by the increased co-localization of AβPP and PP1α (protein phosphatase 1α) at the cell surface upon exposure to OA and PMA. Overall, our results support the notion that signal transduction processes may be of particular relevance for our understanding of the molecular basis of AD, and for the design of rational signal transduction therapeutics. Show more

Keywords: stress, phorbol ester, PP1, protein phosphatase 1

DOI: 10.3233/JAD-2005-7302

Citation: Journal of Alzheimer's Disease, vol. 7, no. 3, pp. 201-212, 2005

Price: EUR 27.50

βII-tubulin and phospho-tau aggregates in Alzheimer's disease and Pick's disease

Authors: Puig, B. | Ferrer, I. | Ludueña, R.F. | Ávila, J.

Article Type: Research Article

Abstract: The expression of βI-, βII- and βIII-tubulin isotypes was examined by immunohistochemistry in the entorhinal and transentorhinal cortices, hippocampus and dentate gyrus in normal human brains and in cases with Alzheimer's disease (AD), Pick's disease (PiD) and in argyrophilic grain disease (AGD). The results showed that βII-tubulin predominated in the upper layers (mainly layer II) and βIII-tubulin in the inner layers of the entorhinal and transentorhinal cortices in control brains. βII-tubulin immunoreactivity was higher than βIII-tubulin immunoreactivity in granular neurons of the dentate gyrus, whereas pyramidal neurons of the hippocampus proper were stained equally with anti-βII-tubulin and βIII-tubulin antibodies. No …preferential layering distribution was observed for βI-tubulin. Polymerization assays with tubulin peptides following the method of microtubule-associated protein displacement demonstrated that the βI and βIII isotypes have a higher binding capacity for tau than does the βII isotype. Interestingly, about 60% of neurons with neurofibrillary tangles in layer II of the entorhinal and transentorhinal cortices in AD were selectively stained with anti-βII-tubulin antibodies. Moderate βII-tubulin immunoreactivity was also observed in Pick bodies in PiD. Taken together, these findings support the view that high βII-tubulin content is a contributing factor in the formation of abnormal hyper-phosphorylated tau aggregates. Show more

Keywords: Alzheimer's disease, Pick's disease, tubulin, tau

DOI: 10.3233/JAD-2005-7303

Citation: Journal of Alzheimer's Disease, vol. 7, no. 3, pp. 213-220, 2005

Price: EUR 27.50

Ineffective phagocytosis of amyloid-β by macrophages of Alzheimer's disease patients

Article Type: Research Article

Abstract: The defective clearance of amyloid-β (Aβ) in the brain of Alzheimer's disease (AD) patients is unexplained. The immunohistochemical studies of the frontal lobe and hippocampus show perivascular and intraplaque infiltration by blood-borne macrophages containing intracellular Aβ but only inefficient clearance of Aβ deposits. Neurons and neuronal nuclei, respectively, express interleukin-1β and the chemokine RANTES, which could induce the inflammatory cell infiltration. To clarify the pathophysiology of Aβ clearance, we examined Aβ phagocytosis by monocytes and macrophages isolated from the blood of age-matched patients and controls. Control monocytes display excellent differentiation into macrophages and intracellular phagocytosis of Aβ followed by Aβ …degradation or export. AD monocytes show poor differentiation and only surface uptake of Aβ and suffer apoptosis. HLA DR and cyclooxygenase-2 are abnormally expressed on neutrophils and monocytes of AD patients. AD patients have higher levels of intracellular cytokines compared to controls. Thus Aβ clearance is not restricted to brain microglia and involves systemic innate immune responses. In AD, however, macrophage phagocytosis is defective, which may elicit compensatory response by the adaptive immune system. Show more

Keywords: macrophage/monocyte, amyloid-beta phagocytosis, macrophage apoptosis, innate immunity, inflammation and Alzheimer's disease

DOI: 10.3233/JAD-2005-7304

Citation: Journal of Alzheimer's Disease, vol. 7, no. 3, pp. 221-232, 2005

Price: EUR 27.50