This proposal presents a strategy to oppose, by inhibition of a single molecule, the three key pathologies of Alzheimer's Disease (AD): namely A/amyloid accumulation, tau hyperphosphorylation/aggregation and inflammation. A dichotomy has arisen in AD research over the past decade between understanding the origins of the disease and finding treatments for it. Even though there is general agreement that A/amyloid accumulation is an early event, drugs and vaccines aimed solely at reducing A/amyloid accumulation have, to date, been unsuccessful at reaching their primary clinical objectives in human trials. In several of these trials, failure was most likely due to intervention in mild or moderate disease, when tau and inflammation are driving neuronal dysfunction and death. In order to continue to target mild/moderate AD it is likely that future treatments may include a combination of drugs that target each of these pathologies and that they will be used together in a cocktail. That scenario may be decades away however, because no effective treatments have been currently approved as disease modifiers for any of these pathologies. An alternative immediate strategy is to development drugs that target all three pathologies simultaneously. This approach, if successful in preclinical and clinical trials, has the great advantage of requiring only one FDA approval rather than one for each of the drugs targeting each of the pathologies. In addition, the modern history of drug development is to target a single molecule rather than many. Both the FDA and major drug companies are comfortable with this approach because side-effects are generally related to the number of targets engaged by a therapeutic molecule. Thus, the engagement of a single target molecule with multiple beneficial downstream effects is desirable from both drug development and regulatory stand points. We have pursued this strategy by first screening for drugs that lower A production, which led us to the discovery of specific dihydropyridines, one of which, nilvadipine, we have now advanced to phase III clinical trials in Europe. In pursuing the mechanism of action of nilvadipine and related A-lowering compounds, we discovered their ability to modestly inhibit spleen tyrosine kinase (Syk) and by this mechanism to inhibit: 1) kinase cascades; 2) NF-kB activation; 3) cytokine production; 4) BACE expression and hence; 5) A production. As Syk was known to directly phosphorylate tau we were interested in the impact of Syk inhibition on tauopathy in relation to AD and have shown that Syk inhibition directly and indirectly reduces tau hyperphosphorylation and also lowers its aggregation. Thus our preliminary data suggest that Syk inhibition reduces three key features of AD; A/amyloid accumulation, tau hyperphosphorylation/aggregation and inflammation in acute treatment paradigms. The purpose of this proposal is to extend these preliminary findings to chronic studies of the impact of potent Syk inhibition on these three pathologies as a proof of concept study. We will use a highly specific Syk inhibitor in transgenic models of Alzheimer's amyloidosis and of tauopathy, both of which have prominent inflammatory features. We wish to examine these pathologies separately at this stage, in order to not confound testing of mechanistic hypotheses by making the models too complex. We have also chosen to intervene in the models once AD related pathologies are well established as we anticipate clinical use of Syk inhibitors in AD in the mild/moderate stage, when many cases of AD present in non specialist centers. We anticipate that we will see highly significant reductions of the known degenerative, inflammatory and behavioral endpoints in these models. These studies will provide the cornerstone for clinical development of Syk inhibitors for the treatment of AD.

Public Health Relevance

Available evidence suggests that there may be over 400,000 new cases of Alzheimer's disease (AD) in veterans by 2020. No drugs are currently approved anywhere in the world that modify the course of the disease. To date, most drugs tested have targeted one molecule, primarily amyloid, and have proved disappointing with several major clinical trial failures. We have discovered that a new target, spleen tyrosine kinase (Syk), regulates the three key aspects of AD pathology, namely A/amyloid accumulation, tau hyperphosphorylation/aggregation and inflammation. We propose here to inhibit Syk with a highly specific and potent drug to demonstrate that the AD related pathology in mouse models will be very significantly reduced. If this is successful, and our initial data suggest it will be, these studies will help validate Syk inhibition as a novel approach to AD treatment and will open the way for clinical trials of Syk inhibitors in man.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Neurobiology D (NURD)
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James A. Haley VA Medical Center
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Schweig, Jonas Elias; Yao, Hailan; Beaulieu-Abdelahad, David et al. (2017) Alzheimer's disease pathological lesions activate the spleen tyrosine kinase. Acta Neuropathol Commun 5:69