c-Abl links APP-BACE1 interaction promoting APP amyloidogenic processing in Niemann-Pick type C disease.

BACKGROUND: Niemann-Pick type C (NPC) disease is characterized by lysosomal accumulation of cholesterol. Interestingly, NPC patients' brains also show increased levels of amyloid-ß (Aß) peptide, a key protein in Alzheimer's disease pathogenesis. We previously reported that the c-Abl tyrosine kinase is active in NPC neurons and in AD animal models and that Imatinib, a specific c-Abl inhibitor, decreased the amyloid burden in brains of the AD mouse model. Active c-Abl was shown to interact with the APP cytosolic domain, but the relevance of this interaction to APP processing has yet to be defined. RESULTS: In this work we show that c-Abl inhibition reduces APP amyloidogenic cleavage in NPC cells overexpressing APP. Indeed, we found that levels of the Aß oligomers and the carboxy-terminal fragment ßCTF were decreased when the cells were treated with Imatinib and upon shRNA-mediated c-Abl knockdown. Moreover, Imatinib decreased APP amyloidogenic processing in the brain of an NPC mouse model. In addition, we found decreased levels of ßCTF in neuronal cultures from c-Abl null mice. We demonstrate that c-Abl directly interacts with APP, that c-Abl inhibition prevents this interaction, and that Tyr682 in the APP cytoplasmic tail is essential for this interaction. More importantly, we found that c-Abl inhibition by Imatinib significantly inhibits the interaction between APP and BACE1. CONCLUSION: We conclude that c-Abl activity facilitates the APP-BACE1 interaction, thereby promoting amyloidogenic processing of APP. Thus, inhibition of c-Abl could be a pharmacological target for preventing the injurious effects of increased Aß levels in NPC disease.

De novo induction of amyloid-ß deposition in vivo.

Alzheimer's disease (AD), the most common type of senile dementia, is associated to the build-up of misfolded amyloid-ß (Aß) in the brain. Although compelling evidences indicate that the misfolding and oligomerization of Aß is the triggering event in AD, the mechanisms responsible for the initiation of Aß accumulation are unknown. In this study, we show that Aß deposition can be induced by injection of AD brain extracts into animals, which, without exposure to this material, will never develop these alterations. The accumulation of Aß deposits increased progressively with the time after inoculation, and the Aß lesions were observed in brain areas far from the injection site. Our results suggest that some of the typical brain abnormalities associated with AD can be induced by a prion-like mechanism of disease transmission through propagation of protein misfolding. These findings may have broad implications for understanding the molecular mechanisms responsible for the initiation of AD, and may contribute to the development of new strategies for disease prevention and intervention.

C-Abl tyrosine kinase signaling: a new player in AD tau pathology.

Hyperphosphorylated tau is a cardinal feature of Alzheimer's disease (AD) pathology. The deregulation of kinases that phosphorylate tau can alter normal tau-related processes, including microtubule dynamics, growth cones, and axonal transport, and induce tau aggregation in paired helical filaments. Here we discuss the possible roles of the Abl family of tyrosine kinases, which are essential regulators of cytoskeleton cellular signaling cascades, in AD tau pathology and how the physiological roles of Abl kinases could be connected with the cytoskeletal alterations induced by Aß aggregates and AD progression.

Disrupting beta-amyloid aggregation for Alzheimer disease treatment.

Alzheimer's disease is a devastating degenerative disorder for which there is no cure or effective treatment. Although the etiology of Alzheimer's disease is not fully understood, compelling evidence indicates that deposition of aggregates composed by a misfolded form of the amyloid beta peptide (Abeta) is the central event in the disease pathogenesis. Therefore, an attractive therapeutic strategy is to prevent or reverse Abeta misfolding and aggregation. Diverse strategies have been described to identify inhibitors of this process, including screening of libraries of small molecules chemical compounds, rational design of synthetic peptides, assessment of natural Abeta-binding proteins and stimulation of the immune system by vaccination. In this article we describe these different approaches, their principles and their potential strengths and weaknesses. Overall the available data suggest that the development of drugs to interfere with Abeta misfolding and aggregation is a feasible target that hold great promise for the treatment of Alzheimer's disease.

Inhibition of protein misfolding and aggregation by small rationally-designed peptides.

Several human diseases are associated with the presence of toxic fibrillar protein deposits. These diseases called protein misfolding disorders, are characterized by the accumulation of misfolded protein aggregates in diverse tissues. Strong evidence indicates that the conversion of a normal soluble protein into a beta-sheet-rich oligomeric structure and further fibrillar aggregation are the key events in the disease pathogenesis. Therefore, a promising therapeutic target consists of the prevention and dissolution of misfolded protein aggregates. Peptides designed to specifically bind to the pathogenic protein and block and/or reverse its abnormal conformational change constitute a new class of drugs. This article reviews this approach, describing diverse compounds reported to have this activity.