Altered Subcellular Distribution of c-Abl in Alzheimer's Disease

Abstract

Abstractc-Abl is a non-receptor tyrosine kinase that participates in multiple signaling pathways linking the cell surface, cytoskeleton, and the nucleus. Recent in vitro studies have also linked c-Abl to amyloid-β-induced toxicity and tau phosphorylation. To further characterize a potential role of c-Abl in Alzheimer's disease (AD), we examined the expression and distribution of total and phosphorylated forms of c-Abl in the hippocampus of AD and control subjects. Laser scanning confocal microscopy was used to examine the colocalization of c-Abl with AD pathology. Our results demonstrate alterations in the presence and distribution of c-Abl and phosphorylated isoforms of c-Abl within the hippocampus during AD. Total unphosphorylated c-Abl was highest in non-demented control hippocampus. Activated isoforms of c-Abl were most abundant in AD hippocampus and co-localized with AD pathology, including granulovacuolar degeneration bodies. c-Abl interacts with phosphorylated tau in AD brain and may contribute to the formation of tau pathology. These studies demonstrate altered activation and distribution of c-Abl during AD, suggesting a role for c-Abl in Aβ signal transduction and generation of tau pathology in AD.

Involvement of c-Abl Kinase in Microglial Activation of NLRP3 Inflammasome and Impairment in Autolysosomal System

“…A growing body of evidence indicates that c-Abl inhibitor could suppress neurotoxicity and neuroinflammation in experimental models of PD and AD (Jing et al, 2009; Estrada et al, 2011; Karuppagounder et al, 2014; Brahmachari et al, 2016). In an effort to assess the anti-inflammatory effects of DAS, a dual c-Abl/c-Src kinase inhibitor (Lombardo et al, 2004), we used the LPS-stimulated BV2 microglial cells as a model of neuroinflammation.…”

“…Interestingly, c-Abl has also been implicated in the CNS development, including neurogenesis, neurite outgrowth, and neuronal plasticity (Moresco and Koleske, 2003; Moresco et al, 2003). A growing body of evidence from several experimental model systems has also demonstrated that c-Abl is activated in neurodegenerative diseases including Alzheimer's disease (Cancino et al, 2008; Jing et al, 2009; Tremblay et al, 2010), Parkinson's disease (Ko et al, 2010; Imam et al, 2011; Mahul-Mellier et al, 2014) and synucleinopathies (Estrada et al, 2011). In this context, c-Abl has been shown to promote tyrosine phosphorylation of parkin in the N-terminal domain, and STI-571, a c-Abl kinase inhibitor has been shown to inhibit tyrosine phosphorylation thereby maintaining in a catalytically active and protective state (Ko et al, 2010).…”

Role of Zinc Metallothionein-3 (ZnMt3) in Epidermal Growth Factor (EGF)-induced c-Abl Protein Activation and Actin Polymerization in Cultured Astrocytes

“…modulation of actin cytoskeleton and c-Abl activation. A growing body of evidence indicates that diverse neurological disorders, including Alzheimer disease and brain ischemia, are accompanied by altered levels of c-Abl and actin (51)(52)(53)(54)(55)(56)(57). Hence, the insight that Mt3 plays a role in c-Abl activation and actin dynamics may suggest new therapeutic strategies for such neurological disorders.…”

Multifunctional Abl kinases in health and disease

“…Recent data have implicated abnormally activated Abl kinases in multiple neurodegenerative diseases (reviewed in Schlatterer et al, 2011) (Jing et al, 2009;Ko et al, 2010). Pharmacological inhibition of Abl kinases in both Alzheimer's disease (AD) and Parkinson's (PD) disease models facilitates amyloid clearance and reduces neuro-inflammation, two key drivers of neuronal cell death.…”