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Presenilin 2 - a protector against Alzheimer's disease

Final Report Summary - BRAINPROTECT (Presenilin 2 - a protector against Alzheimer's disease)

Alzheimer’s disease (AD) is the most prevalent type of dementia in Europe and worldwide. According to the AD International Report for 2010, the number of people suffering from dementia in Europe is estimated to be 9.9 million, with AD patients accounting for the vast majority of these cases. AD is a progressively debilitating disorder for which disease-modifying therapies are lacking. As such, this disease represents an overwhelming physical, psychological and financial burden with regard to healthcare both to the families of patients and the society as a whole. Given the above facts, curing AD represents a worldwide as well as a European need.

The goal of the BrainProtect project was to illuminate novel disease-preventive pathways that could be used for therapeutic prevention of AD and, possibly, other neurodegenerative disorders. We have been intrigued by the fact that one human bran region - cerebellum – is resistant to AD pathology, suggesting that cerebellum may hold key protective factor(s) against AD. In contrast to AD where neurodegeneration primarily occurs in the brain regions of hippocampus and cortex, while cerebellum seems to be protected, in a rare inherited neurodegenerative disorder Niemann-Pick type C (NPC) (caused by mutations in NPC1 or NPC2 genes) Purkinje neurons in the cerebellum are most affected, while hippocampus seems to be spared. Interestingly, while these two neurodegenerative disorders are characterized by clear neuropathological distinctions, recent studies have shown that NPC disease, also named “childhood Alzheimer’s”, shares several key features of AD. Thus, we reasoned that by comparing brain vulnerabilities and molecular events that lead to neurodegeneration between AD and NPC we may identify critical factors(s) involved in protective mechanism(s) against these devastating disorders.

In this project we tested whether presenilin 2 protein (PS2), which is found to be overexpressed in the human cerebellum compared to other brain regions, could be a protective molecule against neurodegeneration, suggesting that PS2-based therapies may represent a novel strategy against AD and, possibly, NPC disease. In a multidisciplinary project performing molecular and cell biological as well as proteomic analyses in vitro (at a cellular level) and in vivo (in a mouse model) as well as in human brain samples, we tested whether PS2 alterations contribute to AD-like phenotype and neurodegeneration in a “childhood Alzheimer’s” and a rare lysosomal disorder - NPC. In parallel, we also analysed the levels of its homologue PS1. Namely, studies of AD have shown that presenilins (PS1 and PS2) may share a common function to generate amyloid-β peptides (Aβ) that accumulate in AD brains and that they, however, may also play distinct roles in different brain regions.

Firstly, we analysed the PS1/2 expression in human brains of healthy and NPC patients, including cerebellum. Secondly, we tested whether alterations of PS1/2 contribute to neurodegeneration in the cerebellum and an AD-like phenotype in a mouse model of NPC disease. Thirdly, we determined whether there are functional link(s) between PS1/2 and NPC1/2 proteins, namely, that PS1/2 may lead to altered NPC1/2 expression and vice versa. Lastly, we aimed to identify other proteins within the PS1/2 and NPC1/2 pathway in order to elucidate novel targets for developing preventive therapies against AD and, possibly, NPC disease.

Our results show that protein levels of PS1 and PS2 in the mouse model of NPC disease are significantly increased in the cerebellum and in the rest of the brain, which is resistant to neurodegeneration, respectively. These novel observations indicate that PS1 and PS2 proteins may serve different functions in different regions of the brain, by regulating vulnerable or protective molecular mechanism(s) of cell death events. Therefore, increased PS2 protein levels in human cerebellum, as shown previously, might serve as a significant resilience factor in the resistance of cerebellum to AD pathology. In conclusion, our results indicate that manipulation of presenilin protein levels in select regions of the brain could increase the brain’s protection against neurodegenerative diseases. This new evidence might have important implications in designing novel therapeutic strategies for the successful treatment of the human Niemann-Pick type C cerebellar neurodegeneration as well as in developing protective therapies against Alzheimer’s disease. As neurodegenerative disorders, AD and NPC, present a great burden for the society, economy and in particular for the affected families we hope that the findings of the BrainProtect project will contribute to a global combat against these devastating disorders.

Silva Katusic Hecimovic, PhD
Division of Molecular Medicine
Ruder Boskovic Institute
Bijenicka c. 54,
10000 Zagreb, CROATIA
Tel: +385-1-4571327