Alzheimer’s disease (AD) is a devastating neurodegenerative disease and the most common cause for dementia. For decades, amyloid beta (Aβ) and tau were considered as the key molecules in AD pathogenesis, therapy and diagnosis but intensive evaluation of these potential therapy targets was disillusioning in clinical trials. As treatment options are still very limited and with minor efficacy, novel disease-modifying, multimodal therapy targets are of immanent socioeconomic value for the aging societies of the world.
Kallikrein-8 as a novel theranostic target in AD
The extracellular serine protease kallikrein-8 (KLK8, alias neuropsin) modulates cognitive functions by the processing of prominent neuroplasticity-related substrates. Our knowledge about the role of KLK8 in neuropathological processes is, however, very limited.
Our lab was the first to demonstrate dysregulated KLK8 signaling in diseased brains from both AD patients and transgenic mice. We found elevated cerebral levels of KLK8 mRNA and protein in the human brain in an early preclinical stage (CERAD A/Braak I-II) when only the first speck of Aβ deposition becomes apparent; in transgenic mouse, the up-regulation was detectable even prior to any Aβ deposition. Interestingly, cerebral KLK8 levels were, regardless of AD pathology, higher in women or female mice as compared to male individuals and in vitro experiments indicated that estrogen might be a trigger for this sex-specific KLK8 overproduction. KLK8 elevation is not only detectable in the brain but also in the blood and CSF of patients with early AD and even stronger with mild cognitive impairment (MCI). In this pilot cross-sectional study the diagnostic performance of CSF and blood KLK8 was relatively comparable and in the case of MCI, in part, even superior to that of the established CSF core biomarkers Aβ42, phospho-tau and total tau.
Intriguingly, we showed that both, short-term, antibody-mediated inhibition of pathologically elevated KLK8 as well as permanent, genetic KLK8 knockdown are capable of attenuating various pathologic features of AD in primary cells and transgenic mice in a sex-specific manner. Fortunately, in wildtype mice with normal physiological KLK8 levels, KLK8 inhibition or knockdown exhibited no or only slightly deteriorating effects on few parameters.
Together, these findings highlight KLK8 as a potential antecedent biomarker and therapeutic target in AD. Ongoing and future studies aim to validate the theranostic potential of KLK8 in order to translate KLK8 from bench to bedside.
Transgenerational effects of exercise on AD
A physically and mentally stimulating lifestyle tremendously reduces the risk of dementia and slows the cognitive decline in AD patients. First, it was assumed that training solely improves brain plasticity by increasing the cognitive reserve and thereby compensates functional deficits.
Experimental animal studies from our and other labs have though provided evidence that a stimulating environmental enrichment (EE) further interferes with the pathomechanisms of AD. Additionally, we demonstrated that EE exerts beneficial effects over a very extended period of ontogenesis, from in utero stimulation via maternal running during pregnancy until late exercise in a full-blown disease stage, and that the time point when enrichment starts determines the molecular mechanisms that conduct resistance to AD pathology.
Whether EE-induced protective effects against AD might even be transgenerationally inherited across several generations and if so, what epigenetic modifications enable maternal/paternal transmission are questions we currently aim to answer.
Funding: Deutsche Forschungsgemeinschaft (DFG), European Regional Development Fund (EFRE)
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Multiple sclerosis (MS) is the most frequent demyelinating disease of the central nervous system (CNS). It affects approximately 2.8 million people worldwide with major individual and socio-economic consequences. MS lesions are characterized by chronic inflammation, demyelination, attenuated remyelination and axonal loss. The latter is considered the main reason for permanent clinical disability of patients. A deeper understanding of the above named pathophysiological processes is necessary for developing more efficient therapeutic approaches.
The Role of deregulated microRNAs in grey and white matter lesions
MicroRNAs are endogenous 19–25 nucleotide RNAs that have emerged as a novel class of important gene-regulatory molecules involved in many critical developmental and cellular functions. The aim of this projects is to better understand the role of deregulated microRNAs in grey and white matter lesions as well as their impact on dysregulatedcytokine milieu within the demyelination areas.
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- Gerdes, L.A., Held, K., Beltrán, E., Berking, C., Prinz, J.C., Junker, A., Tietze, J.K., Ertl-Wagner, B., Straube, A., Kümpfel, T., Dornmair, K. & Hohlfeld, R. CTLA4 as Immunological Checkpoint in the Development of Multiple Sclerosis. Ann Neurol 80, 294-300.
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- Junker, A., Ivanidze, J., Malotka, J., Eiglmeier, I., Lassmann, H., Wekerle, H., Meinl, E., Hohlfeld, R. & Dornmair, K. Multiple sclerosis: T-cell receptor expression in distinct brain regions. Brain 130, 2789-99.
- Krumbholz, M., Theil, D., Steinmeyer, F., Cepok, S., Hemmer, B., Hofbauer, M., Farina, C., Derfuss, T., Junker, A., Arzberger, T., Sinicina, I., Hartle, C., Newcombe, J., Hohlfeld, R. & Meinl, E. CCL19 is constitutively expressed in the CNS, up-regulated in neuroinflammation, active and also inactive multiple sclerosis lesions. J Neuroimmunol 190, 72-79.
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Diffuse astrocytomas are the most common adult-type primary brain tumors harboring an intrinsic capacity for malignant progression to glioblastomas (GBM). GBM is a fatal disease with a median survival of 15-18 months after diagnosis and since GBM is highly resistant to therapy, survival times increase only modest upon maximal care.
The role of Kallikrein-8 in the pathophysiology of diffuse astrocytomas
The aim of this project is to investigate the role of KLK8 in the pathophysiology of diffuse astrocytic tumors and to verify whether KLK8 might bear the capacity to serve as a therapeutic target.
Work in progress