Forschung


Major research areas are as follows:

 

• Intraindividual and transgenerational epigenetic effects of exercise on Alzheimer pathology

A physically and mentally stimulating lifestyle reduces the risk of developing dementia and slows the cognitive decline in humans with Alzheimer's disease (AD). Until a few ago it was assumed that plastic changes of the brain triggered by training increase the so-called cognitive reserve and thereby compensate functional deficits. Experimental animal studies from our and other working groups have though provided evidence that a cognitively and/or physically stimulating environmental enrichment further interferes with the pathomechanisms of AD. In transgenic mice with an AD-like pathology enrichment not only improves learning and memory performances but also reduces cerebral beta-Amyloid (Aβ) deposits, diminishes oxidative stress, modulates immune reaction, improves neurovascular functionality, and increases hippocampal neurogenesis (Fig.). Furthermore we could demonstrate that both therapeutic as well as preventive enrichment counteracts AD-like pathology, although by different molecular mechanisms. Moreover, a recent study from our lab shows that even prenatal stimulation (running during pregnancy) can antagonize AD-associated changes of the (offspring's) brain.
We now sought to understand how these behavioral changes of the individual itself or their mothers result (within one generation or from one to the next) in structural and molecular modifications of the AD-affected brain and aim to decipher the underlying epigenetic mechanisms of these effects.


• Reelin-dependent transmembrane signaling in AD

Reelin regulates nervous system development and modulates synaptic plasticity in the adult brain. Several findings suggest that alterations in Reelin signaling may contribute to neuronal dysfunction associated with AD. The aim of this project is to find out whether Reelin signaling is disturbed in Alzheimer diseased brain, and if yes, whether this is a cause or a consequence of AD. To answer these questions the expression pattern of Reelin signaling molecules will be examined in AD-related areas of human and mouse brain in different stages of the disease. Further, Reelin levels and its glycosylation pattern will be compared in the CSF and plasma of AD patients with those of controls. The functional role of Reelin deficiency will be studied in a transgenic mouse model of AD with or without Reelin deficiency. And last, the effect of exogenous Reelin on Alzheimer pathology will be studied.

 

• Ephrin signaling in AD

Ephrin signaling is essential for multifaceted pathways involved in coordinating axonal guidance, synaptogenesis, synapse-astrocyte interactions, cerebral angiogenesis and autophagy as well as amygdala-generated anxiety – functions which are flawed or attenuated in the context of AD.
The objectives of this study are to find out: whether Ephrin signaling is disturbed as a cause or a consequence of disease in AD brain; whether beneficial effects of exercise are triggered via the Ephrin cascade; whether preventive and therapeutic cerebral administration of different Ephrin signaling agonists / antagonists ameliorates AD-related Aβ pathology, neuronal and neurovascular dysfunction, defective autophagy, cognitive decline and excessive anxiety.

 


Related publications

 

1. Herring A, Münster Y, Akkaya T, Moghaddam S, Deinsberger K, Meyer J, Zahel J, Sanchez-Mendoza E, Wang Y, Hermann DM, Arzberger T, Teuber-Hanselmann S, Keyvani K. Kallikrein-8 inhibition attenuates Alzheimer's pathology in mice. Alzheimers Dement. 2016, pii: S1552-5260(16)30280-1

 

2. Herring A, Münster Y, Metzdorf J, Bolczek B, Krüssel S, Krieter D, Yavuz I, Karim F, Roggendorf C, Stang A, Wang Y, Hermann DM, Teuber-Hanselmann S, Keyvani K. Late running is not too late against Alzheimer's pathology. Neurobiol Dis. 2016, 14:94:44-54.

 

3. Müller-Schiffmann A, Herring A, Abdel-Hafiz L, Chepkova AN, Schäble S, Wedel D, Horn AH, Sticht H, de Souza Silva MA, Gottmann K, Sergeeva OA, Huston JP, Keyvani K, Korth C. Amyloid-β dimers in the absence of plaque pathology impair learning and synaptic plasticity. Brain. 2016, 139:509-25.

 

4. Herring A, Donath A, Steiner KM, Widera MP, Hamzehian S, Kanakis D, Kölble K, ElAli A, Hermann DM, Paulus W, Keyvani K. Reelin depletion is an early phenomenon of Alzheimer pathology. J Alzheimers Dis. 2012, 30:963-79


5. Herring A, Donath A, Yarmolenko M, Uslar E, Conzen C, Kanakis D, Bosma C, Worm K, Paulus W, Keyvani K. Exercise during pregnancy mitigates Alzheimer-like pathology in mouse offspring. FASEB J. 2012, 26:117-128.

 

6. Dodel R, Balakrishnan K, Keyvani K, Deuster O, Neff F, Andrei-Selmer LC, Röskam S, Stüer C, Al-Abed Y, Noelker C, Balzer-Geldsetzer M, Oertel W, Du Y, Bacher M. Naturally occurring autoantibodies against beta-amyloid: investigating their role in transgenic animal and in vitro models of Alzheimer's disease. J Neurosci. 2011, 31:5847-54.

 

7. Herring A, Lewejohann, L, Panzer AL, Donath A, Kröll O, Sachser N, Paulus W, Keyvani K. Preventive and therapeutic types of environmental enrichment counteract beta amyloid pathology by different molecular mechanisms. Neurobiol Dis. 2011, 42:530-538.

 


8. Herring A, Blome M, Ambrée O, Sachser N, Paulus W, Keyvani K. Reduction of Cerebral Oxidative Stress Following Environmental Enrichment in Mice with Alzheimer-Like Pathology. Brain Pathol. 2010 20:166-75.


9. Herring A, Ambrée O, Tomm M, Habermann H, Sachser N, Paulus W, Keyvani K. Environmental enrichment enhances cellular plasticity in transgenic mice with Alzheimer-like pathology. Exp Neurol. 2009, 216:184-92.


10. Ambrée O, Richter H, Sachser N, Lewejohann L, Dere E, de Souza Silva MA, Herring A, Keyvani K, Paulus W, Schäbitz WR. Levodopa ameliorates learning and memory deficits in a murine model of Alzheimer`s disease. Neurobiol Aging. 2009, 301192-204.


11. Bacher M, Dodel R, Aljabari B, Keyvani K, Marambaud P, Kayed R, Glabe C, Goertz N, Hoppmann A, Sachser N, Klotsche J, Schnell S, Lewejohann L, Al-Abed Y. CNI-1493 inhibits Abeta production, plaque formation, and cognitive deterioration in an animal model of Alzheimer`s disease. J Exp Med. 2008, 205:1593-9.


12. Görtz N, Lewejohann L, Tomm M, Ambrée O, Keyvani K, Paulus W, Sachser N.
Effects of environmental enrichment on exploration, anxiety, and memory in female TgCRND8 Alzheimer mice. Behav Brain Res. 2008,191:43-8


13. Herring A, Yasin H, Ambrée O, Sachser N, Paulus W, Keyvani K.
Environmental enrichment counteracts Alzheimer`s neurovascular dysfunction in TgCRND8 mice. Brain Pathol. 2008, 18:32-9.


14. Ambrée O, Leimer U, Herring A, Görtz N, Sachser N, Heneka MT, Paulus W, Keyvani K. Reduction of amyloid angiopathy and Abeta plaque burden after enriched housing in TgCRND8 mice: involvement of multiple pathways. Am J Pathol. 2006, 169:544-52.


15. Ambrée O, Touma C, Görtz N, Keyvani K, Paulus W, Palme R, Sachser N. Activity changes and marked stereotypic behavior precede Abeta pathology in TgCRND8 Alzheimer mice. Neurobiol Aging. 2006, 27:955-64.


16. Schwarze-Eicker K, Keyvani K, Görtz N, Westaway D, Sachser N, Paulus W.
Prion protein (PrPc) promotes beta-amyloid plaque formation. Neurobiol Aging. 2005, 26:1177-82


17. Touma C, Ambrée O, Görtz N, Keyvani K, Lewejohann L, Palme R, Paulus W, Schwarze-Eicker K, Sachser N. Age- and sex-dependent development of adrenocortical hyperactivity in a transgenic mouse model of Alzheimer`s disease.  Neurobiol Aging. 2004, 25:893-904.