Investigation of cerebral amyloidosis and associated pathology in the olfactory bulb of a mouse model of Dementia with Lewy bodies

• Applicant: Professorin Dr. Melanie Meyer-Luehmann
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 323695292

Amyloid b (Ab) plaques and Lewy bodies mainly composed of a-synuclein (a-syn) are the major neuropathological hallmarks of Alzheimers disease (AD) and Parkinsons disease (PD), respectively. Moreover, these protein deposits frequently co-exist in most cases of Dementia with Lewy bodies (DLB), and in 50% of AD cases. In the brains of these patients, a-syn does not only accumulate in Lewy bodies but also in dystrophic neurites decorating Ab plaques. Neurodegenerative diseases are often accompanied by a loss of smell, and in case of Alzheimers and Parkinsons disease, an impaired sense of smell is one of the earliest symptoms. Loss of olfaction might result from changes at both, the anatomical and molecular level. However, the cellular and molecular mechanism for this olfactory deficit is still unknown. The objective of this application is to characterize cerebral amyloidosis in the olfactory bulb of APP x a-synA30P transgenic mice which serve as a model for DLB. To this end, we plan to analyze Ab plaque load and associated neuronal and glial changes (with a focus on microglia) in the olfactory bulb of APP x a-synA30P transgenic mice. Furthermore, this approach will be complemented by behavioral examinations of APP x a-synA30P transgenic mice and the respective single-transgenic control mice to determine the functional consequences thereof. Moreover, it is intended to study the kinetics of concomitant a-syn and Ab pathology in wildtype (wt) non-transgenic grafts transplanted into APP x a-synA30P transgenic mice. Thus, by identifying which lesion manifests first, we finally will be able to decipher if and how both proteins might influence each others aggregation properties. Therefore, this study could provide not only important insights into the pathogenesis of neurodegenerative diseases with co-existing Ab and a-syn deposits but also valuable insight for the development of effective therapeutics.

• DFG Programme: Research Grants