Abstract
Tyrosine kinase inhibitors (TKIs) are effective therapies for leukaemia. Alzheimer is a neurodegenerative disease characterized by accumulation of β-amyloid (plaques) and hyper-phosphorylated Tau (tangles). Here we show that AD animals have high levels of insoluble parkin and decreased parkin-Beclin-1 interaction, while peripheral administration of TKIs, including Nilotinib and Bosutinib, increases soluble parkin leading to amyloid clearance and cognitive improvement. Blocking Beclin-1 expression with shRNA or parkin deletion prevents tyrosine kinase (TK) inhibition-induced amyloid clearance, suggesting that functional parkin-Beclin-1 interaction mediates amyloid degradation. Isolation of autophagic vacuoles (AVs) in AD mouse brain shows accumulation of parkin and amyloid, consistent with previous results in AD brains, while Bosutinib and Nilotinib increase parkin-Beclin-1 interaction and result in protein deposition in the lysosome. These data suggest that decreased parkin solubility impedes parkin-Beclin-1 interaction and amyloid clearance. We identified two FDA-approved anti-cancer drugs as potential treatment for AD.Two FDA-approved tyrosine kinase inhibitor drugs, Bosutinib and Nilotinib, are shown to ameliorate Alzheimer's disease pathology in mouse models by increasing soluble parkin and leading to amyloid clearance and cognitive improvement.
Highlights
Available tyrosine kinase inhibitors (TKIs), such as Imatinib, are effective in many patients with Philadelphia chromosome‐ positive chronic myelogenous leukaemia (CML) in chronic phase
Tyrosine kinase inhibition restores parkin‐Beclin‐1 interaction To determine whether Tyrosine kinase inhibitors (TKIs) enter the brain, we intraperitoneally (IP) injected 2 months old C57BL6 mice with 10 mg/kg Imatinib, 10 mg/kg Nilotinib and 5 mg/kg Bosutinib in 30 mL DMSO and sacrificed the animals 2–24 h post‐injection
No changes were detected in LC3‐I levels compared to MAP‐2 in Tg‐Amyloid precursor protein (APP) mice (Fig 1B), but LC3‐II, which indicates the amount of autophagosomes, was detected and Bosutinib significantly decreased LC3‐II relative to both LC3‐I (16 Æ 2.4, mean Æ sd, p 1⁄4 0.0001) and MAP‐2 (29 Æ 8, mean Æ sd, p 1⁄4 0.0001) levels (Fig 1B, N 1⁄4 9), suggesting that Abl inhibition increases parkin and facilitates autophagic clearance
Summary
Available tyrosine kinase inhibitors (TKIs), such as Imatinib, are effective in many patients with Philadelphia chromosome‐ positive chronic myelogenous leukaemia (CML) in chronic phase (de Lavallade et al, 2008; Kantarjian et al, 2007). Nilotinib was approved by the US Food and Drug Administration (FDA) in 2007 for CML treatment (300–400 mg orally twice daily) (Deremer et al, 2008; Mahon et al, 2008; Skorski, 2011). Parkin is inactivated in the nigrostriatum of post‐mortem sporadic PD patients (Ko et al, 2010; Lonskaya et al, 2012a), and decreased parkin solubility is associated with defects in autophagic clearance of b‐ amyloid and p‐Tau in post‐mortem Alzheimer’s disease (AD) brains (Lonskaya et al, 2012c). Parkin mediates autophagic degradation of defective mitochondria (mitophagy) (Geisler et al, 2010; Narendra et al, 2008; Park et al, 2009; Vives‐Bauza et al, 2010), and clears autophagic vacuoles (AVs) in AD and PD models (Khandelwal et al, 2011; Lonskaya et al, 2012a; Lonskaya et al, 2012c), while parkin deletion exacerbates amyloid pathology in AD models (Perucho et al, 2010; Rodriguez‐Navarro et al, 2008)
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