'EASIdig' : a digital tool to document disease activity in atopic dermatitis

Different scoring systems have been developed to determine the severity of atopic dermatitis (AD); the SCORAD (Scoring Atopic Dermatitis) and EASI (Eczema Area and Severity Index) are among the best-validated scoring systems. Objective: The aim of this study was to produce a rational quality control for routine clinical use by using the modern facilities of digital imaging. Methods: 63 AD patients were scored by a single person at each visit using the SCORAD and EASI scoring methods. Images were taken and rated by two non-dermatology physicians trained in the scoring system. In addition, blood samples were taken for the determination of total IgE, eosinophils and eosinophilic cationic protein. Results: The EASI score established from the digital images, hereby named ‘EASIdig’, correlated at all visits with the results of the SCORAD and EASI. Together with immunological parameters, they also reflected changes of disease severity during the 3 time points. Conclusion: The digital evaluation of the EASI is a reliable tool for the digital assessment of severity and extent of AD

Proteolytical processing of mutated human amyloid precursor protein in transgenic mice

The evidence that betaA4 is central to the pathology of Alzheimer's disease (AD) came from the identification of several missense mutations in the amyloid precursor protein (APP) gene co-segregating with familial AD (FAD). In an attempt to study the proteolytical processing of mutated human APP in vivo, we have created transgenic mice expressing the human APP695 isoform with four FAD-linked mutations. Expression of the transgene was controlled by the promoter of the HMG-CR gene. Human APP is expressed in the brain of transgenic mice as shown by Western blot and immunohistology. The proteolytic processing of human APP in the transgenic mice leads to the generation of C-terminal APP fragments as well as to the release of betaA4. Despite substantial amounts of betaA4 detected in the brain of the transgenic mice, neither signs of Alzheimer's disease-related pathology nor related behavioural deficits could be demonstrated

Expression of human FE65 in Amyloid Precursor Protein transgenic mice is associated with a reduction in beta-Amyloid load

International audienceFE65 is an adaptor protein that interacts with the cytoplasmic tail of the amyloid precursor protein (APP). In cultured non-neuronal cells, the formation of the FE65-APP complex is a key element for the modulation of APP processing, signalling and beta-amyloid (Abeta) production. The functions of FE65 in vivo, including its role in the metabolism of neuronal APP, remain to be investigated. In this study, transgenic mice expressing human FE65 were generated and crossbred with APP transgenic mice, known to develop Abeta deposits at 6 months of age. Compared with APP mice, APP/FE65 double transgenic mice exhibited a lower Abeta accumulation in the cerebral cortex as demonstrated by immunohistochemistry and immunoassay, and a lower level of APP-CTFs. The reduced accumulation of Abeta in APP/FE65 double transgenics, compared with APP mice, could be linked to the low Abeta42 level observed at 4 months of age and to the lower APP-CTFs levels. The present work provides evidence that FE65 plays a role in the regulation of APP processing in an in vivo model

Hippocampal Neuron Loss Exceeds Amyloid Plaque Load in a Transgenic Mouse Model of Alzheimer’s Disease

According to the “amyloid hypothesis of Alzheimer’s disease,” β-amyloid is the primary driving force in Alzheimer’s disease pathogenesis. Despite the development of many transgenic mouse lines developing abundant β-amyloid-containing plaques in the brain, the actual link between amyloid plaques and neuron loss has not been clearly established, as reports on neuron loss in these models have remained controversial. We investigated transgenic mice expressing human mutant amyloid precursor protein APP751 (KM670/671NL and V717I) and human mutant presenilin-1 (PS-1 M146L). Stereologic and image analyses revealed substantial age-related neuron loss in the hippocampal pyramidal cell layer of APP/PS-1 double-transgenic mice. The loss of neurons was observed at sites of Aβ aggregation and surrounding astrocytes but, most importantly, was also clearly observed in areas of the parenchyma distant from plaques. These findings point to the potential involvement of more than one mechanism in hippocampal neuron loss in this APP/PS-1 double-transgenic mouse model of Alzheimer’s disease

Massive CA1/2 Neuronal Loss with Intraneuronal and N-Terminal Truncated Aβ(42) Accumulation in a Novel Alzheimer Transgenic Model

Alzheimer’s disease (AD) is characterized by a substantial degeneration of pyramidal neurons and the appearance of neuritic plaques and neurofibrillary tangles. Here we present a novel transgenic mouse model, APP(SL)PS1KI that closely mimics the development of AD-related neuropathological features including a significant hippocampal neuronal loss. This transgenic mouse model carries M233T/L235P knocked-in mutations in presenilin-1 and overexpresses mutated human β-amyloid (Aβ) precursor protein. Aβ(x-42) is the major form of Aβ species present in this model with progressive development of a complex pattern of N-truncated variants and dimers, similar to those observed in AD brain. At 10 months of age, an extensive neuronal loss (>50%) is present in the CA1/2 hippocampal pyramidal cell layer that correlates with strong accumulation of intraneuronal Aβ and thioflavine-S-positive intracellular material but not with extracellular Aβ deposits. A strong reactive astrogliosis develops together with the neuronal loss. This loss is already detectable at 6 months of age and is PS1KI gene dosage-dependent. Thus, APP(SL)PS1KI mice further confirm the critical role of intraneuronal Aβ(42) in neuronal loss and provide an excellent tool to investigate therapeutic strategies designed to prevent AD neurodegeneration