The Contribution of Spleen Tyrosine Kinase to the Pathobiology of Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disease that accounts for most cases of dementia. The pathological hallmarks of AD include extracellular A-beta plaques, intracellular tau accumulations or neurofibrillary tangles, as well as neuroinflammation. As of 2018, there exists no disease modifying treatment for AD and the cause of sporadic AD remains elusive. We investigated the contribution of the spleen tyrosine kinase (SYK) in AD pathobiology. Syk is wellknown for its involvement in B-cell receptor (BCR) signaling but our previous data have demonstrated that SYK is also involved in tau yperphosphorylation and A-beta production, therefore suggesting that SYK could contribute to the formation of AD pathological lesions.<br></br><br></br>The goals of our present studies were to determine whether SYK activation occurs in the brain of mouse models of AD and investigate whether the levels of SYK activation vary with the amount of AD pathological lesions. In addition, we aimed to examine the role of SYK in the autophagic degradation of tau via the mammalian target of rapamycin (mTOR) pathway <i>in vitro</i> and <i>in vivo</i>. We investigated SYK activation in different age-groups of A-beta and tau overexpressing mice, as well as human AD specimens. We characterized the activation of SYK in relation to AD pathological lesions including amyloid plaques, activated microglia and astroglia, as well as hyperphosphorylated tau. In addition, our mechanistic <i>in vitro</i> experiments delineated SYK as a regulator of autophagic tau degradation via the mTOR pathway. These data were confirmed in an <i>in vivo</i> study, assessing the effects of a 12-week chronic SYK inhibition on tau burden, neurodegeneration, behavior, and neuroinflammation in a mouse model with established tauopathy.<br></br><br></br>Identifying new targets like SYK that act downstream of A-beta and tau and in turn exacerbate these known pathologies, is crucial to find a treatment for AD.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

The Open University

Year dc:date.issued

2018

Author dc:creator

• Schweig, Jonas Elias

Language dc:language

en