Neuroscience 2017

Birgit Hutter-Paier, Ainara Lopez*, Vera Niederkofler, Stefanie Flunkert, Ewald Auer, Joerg Neddens*

QPS Austria GmbH, Parkring 12, 8074 Grambach, Austria

*contributed equally

Background:
Alzheimer´s disease (AD) is a progressive neurodegenerative disease that leads to neuropathology in the brain. Major hallmarks of the disease are deposition of beta-amyloid in neuritic plaques and formation of neurofibrillary tangles of hyperphosphorylated tau. Published research suggests associations between AD and functional impairments of sensory systems. Recently, the occurrence of Tau-mediated glaucoma has been reported, as well as AD protein-associated neuropathology in sensory systems. The current study is designed to analyze pathological changes in different transgenic rodent models of AD.

Methods:
Eyes and brains were collected from 6 and 12 months old APP rats, TAU rats and TMHT mice. Tissue was cryosectioned and analyzed for neuropathological features like Abeta and Tau expression, neuroinflammation using marker against activated microglia and astrogliosis and well as neurotransmitter level changes. For immunohistochemical analyses, uniform systematic random sets of cryosections were immunofluorescently labeled and retina and olfactory bulb quantitatively analyzed for 6E10, PHF-tau, tau, GFAP, Iba1, ChAT, GAD67 and TH expression.

Results:
We will show data on age-associated pathology in the different rodent models.

Conclusions:
A major focus during interpretation of the data will be to find common pathology features that are associated with the expression of specific human proteins.

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Ewald Auer, Martina Farcher, Roland Rabl, Stefanie Flunkert, Maria Posch, Birgit Hutter-Paier

QPS Austria GmbH, Parkring 12, 8074 Grambach, Austria

Background:
Gaucher disease is the most common lysosomal storage disease. The neuronal disease variant is characterized by aggregated protein accumulations in the brain and associated neurological manifestations. The disease is autosomal recessively inherited and modeled by 4L/PS-NA mice that express low levels of prosaposin and saposins, as well as beta-glucocerebrosidase (GCase) with a point mutation at V394L/V394L. Mutations of GCase are common risk factors for the development of synucleinopathies like Parkinson’s disease or dementia with Lewy bodies. To use 4L/PS-NA mice for compound tests against the Gaucher disease or alpha-synuclein aggregation diseases, a detailed characterization of these mice is needed. We thus analyzed 4L/PS-NA mice for their neuropathological features.

Methods:
4L/PS-NA mice were histologically analyzed for murine alpha-synuclein and GCase expression, neuroinflammation using astroglios and microgliosis marker GFAP and Iba1 as well as ubiquitination. Additionally, animals were analyzed for general health and behavioral deficits using different activity and motor tests.

Results:
Our results show that 4L/PS-NA mice present with progressively increasing murine alpha-synuclein aggregation levels and strong neuroinflammation. The health and behavioral analysis shows that 4L/PS-NA mice have a lower body weight and temperature as well as motor deficits as analyzed with the wire suspension test. Analysis of 4L/PS-NA mice in the Open Field test revealed a reduced rearing behavior.

Conclusions:
In summary 4L/PS-NA mice present with highly increased alpha-synuclein aggregation, related neuroinflammation as well as physiological and behavioral changes. Since the effect on alpha-synuclein protein aggregation must be indirect, these results imply that 4L/PS-NA mice are a good ,em>in vivo model to test new anti-aggregatory compounds against endogenous proteins.

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