Ariad Pharmaceuticals Inc fka ARIA

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The Case for Pona in Alzheimer's...

Now that we have stirred the pot on Parkinsons, let's not overlook the even bigger elephant in the neurogenerative room. This study was published online on 7.4.13 and makes a strong case for use of TKI's (Nilotinib & Bosutinib) in Alzheimer's Disease. Summary of study excerpted below.


http://onlinelibrary.wiley.com/doi/10.1002/emmm.201302771/full



The paper explained

PROBLEM

Alzheimer's disease (AD) is an aging disorder that leads to memory loss. AD is characterized by intraneuronal tangles containing hyper-phosphorylated Tau (p-Tau) and extracellular ß-amyloid (Aß) plaques, derived from amyloid precursor protein (APP) cleavage and accumulation of Aß. Abl is found within neuritic plaques and neurofibrillary tangles (NFTs) and activated (via phosphorylation) in AD post-mortem brains. Src tyrosine kinase (TK) is also recognized in AD pathology via interaction with Tau. Abl inhibition prevents Aß1–42 fibrils and hydrogen peroxide (H2O2)-induced cell death, and hippocampal injection of Aß fibrils leads to an increase of Abl levels. These data led to the hypothesis that tyrosine kinase inhibitors (TKIs) will activate parkin and facilitate autophagic amyloid clearance, thus preventing cognitive decline in AD models. We used several TKIs, including Bosutinib and Nilotinib, which penetrate the brain and induce autophagy in AD models and evaluated the effects of TKIs on parkin-mediated autophagic amyloid clearance in AD models.

RESULTS

We identified two FDA-approved drugs, Bosutinib and Nilotinib, as potential therapies for AD. Our results indicate that decreased parkin solubility decreases functional interaction with a key autophagy molecule, Beclin-1, while TKIs reverse parkin-Beclin-1 interaction in AD models, leading to autophagic clearance of amyloid proteins. TKI-induced decrease of intraneuronal Aß1–42 led to plaque disappearance while lentiviral production of intraneuronal Aß1–42 resulted in plaque formation. Importantly, parkin is required for autophagosome maturation and autophagic clearance and TKIs enhance amyloid clearance and cognitive performance in a parkin-dependent manner.

IMPACT

Our studies show that TKI could be a therapeutic strategy, via degradation of amyloid proteins, in neurodegenerative diseases, including AD. We identified two FDA-approved drugs as potential therapies for AD. TKIs are well tolerated in human leukaemia patients and could be used with a smaller dose over a longer period of time to prevent progression from mild cognitive impairment (MCI) to AD.