RPDOC - Retour Post-Doctorants

Regulation of presynaptic activity by gamma-secretase in Alzheimer’s disease – PreAD

Regulation of neuronal activity by gamma-secretase: an enzyme involved in Alzheimer's disease

Alzheimer's disease is characterized by a synaptic failure and recent data suggest that gamma-secretase, an enzyme involved in Alzheimer's disease, regulates neurotransmitter release at the synaptic level. This project aims to understand how gamma-secretase controls synaptic function.

To identify the mechanism of synaptic failure in Alzheimer's disease

Alzheimer's disease is the most widespread form of dementia and today no curative treatment is available. Synaptic damage and loss are the best correlates of cognitive impairment in Alzheimer's disease.<br />Presenilin, a gene mutated in familial form of Alzheimer's disease, is the catalytic subunit of gamma-secretase enzyme which cleaves numerous synaptic proteins including APP and N-cadherin. This proteolysis releases into the cytosol C-terminal domains which regulate physiological function like transcription. Presenilin mutations associated with early onset form of Alzheimer's disease impair proteolytic activity of gamma-secretase which decreases production of functional peptides and in the same time triggers accumulation of gamma-secretase substrates potentially deleterious. Presenilin participates to presynaptic activity by mechanisms still unknown. This project aims to understand how impairment of gamma-secretase proteolytic activity modifies synaptic function and participates to cognitive deficits. The goal of this project is to study presenilin role in synaptic functions and in hippocampal plasticity which plays a key role in memory encoding. This project involves a new mouse model which does not express presenilin in hippocampus.<br />

To study the presynaptic role of presenilin this project involves a new mouse line which does not express presenilin in dentate gyrus and mossy fibers, a region crucial for memory.
This project combines the expertise of the project leader in molecular and cellular biology of gamma-secretase with new techniques of imaging and optophysiology developed in the host lab. The selected approach enables to distinguish the role of each factor of gamma-secretase enzymatic system. Thus, gamma-secretase substrates will be expressed in granules cells of hippocampus to identify which one contributes the most to synaptic activity. In a similar manner, peptides mimicking products of proteolysis of gamma-secretase substrates will be expressed in granules cells to study their effects on presynaptic activity. In the mouse line that does not express presenilin, we will reexpress mutated presenilin to study how mutations of early-onset Alzheimer's disease impair neurotransmission. This approach will enable to know if accumulated substrates or reduced products associated with mutations of presenilin participate in synaptic impairment of Alzheimer's disease.
This method will be combined to techniques like electrophysiology to record neuronal activity and microscopy to observe the form and state of mossy fibers in mice that lack presenilin.

This new project led to preliminary results that needs further controls. The first series of experiment of this project aimed to study the effect of pharmacological inhibition of gamma-secretase on synaptic transmission. Electrophysiological experiments on hippocampal slices revealed that inhibition of gamma-secretase decrease probability of neurotransmitter release at the mossy fiber to pyramidal cell synapse.

This project aiming to understand the mechanism leading to synaptic functions impairment could help to identify new therapeutic targets to treat Alzheimer disease.

This project started only six months ago has not yet led to scientific publication.

Alzheimer's disease (AD) is the most widespread form of dementia affecting more than 35 millions of individuals. No curative treatment is available and costs of palliative treatments represent a major economic burden in developed countries, in addition to the devastating familial impact. AD is characterized by progressive deterioration of memory and cognitive functions associated with synaptic loss and neurodegeneration in various brain structures, mainly cortex and hippocampus.
Despite intense efforts of research, the etiology is still unknown. Rare inherited cases of AD (Familial Alzheimer’s Disease: FAD) revealed the important role of a proteolytic enzyme: the gamma-secretase. More than 150 mutations have been found along the gene of presenilin (PS) that forms the catalytic subunit of the gamma-secretase proteolytic complex. gamma-secretase promotes the cleavage of a large number of cell surface proteins including APP, Notch1, cadherins and ephrins at the membrane/cytosol interface, called epsilon-site. It has been demonstrated by Dr Robakis’s laboratory, where I perform my post-doctoral training, that gamma-secretase cleavage at the epsilon-site produces peptides (IntraCellular Domains: ICDs or CTF2) that have specific signal transduction and transcriptional properties Mutations of PS causing FAD impair the proteolytic activity of gamma-secretase at the epsilin-site of many substrates including Notch, N-cadherin, ephrinB. As a consequence, PS mutations in FAD decrease the production of signaling peptides with potential biological functions and also trigger accumulation of membrane-bound substrates (or stubs) which may be deleterious.
Synaptic dysfunction and loss are the best pathological correlates of cognitive impairment in AD. Recent evidence suggests that presenilin loss of function may contribute to the impairment of synaptic circuits and to the cognitive deficits. Conditional mutations of PS in the mouse revealed that absence of PS at the presynapse, but not at the postsynapse, impairs short and long term synaptic plasticity in the CA1 region of the hippocampus. The molecular mechanisms by which the loss of function of PS impairs synaptic plasticity remain to be explored. Various cellular functions regulated by PS or one of its substrates could be affected, for example signaling and transcription by ICDs, trafficking by APP-partners, regulation of Ca2+ homeostasis by presenilin itself.
The basic research project that I will develop focuses on the study of the mechanism by which loss-of function of PS impacts on synaptic plasticity, at an identified synapse of the hippocampus, which plays a key role in encoding memory: the synapse between mossy fibers from the dentate gyrus and CA3 pyramidal neurons.
I will generate a new line of transgenic mice with a postnatal deletion of the PS restricted to cells of the dentate gyrus. I will characterize the impact of the invalidation of PS at mossy fiber to CA3 synapses, in terms of properties and synaptic plasticity, of presynaptic calcium signaling in mossy fiber terminals, and finally in terms of ultrastructural properties of synapses (eg location of synaptic vesicles).
Through molecular re-expression approaches by gene transfer in vivo, followed by a functional analysis, I will analyze the mechanisms leading to presynaptic dysfunction in case of invalidation or mutations of PS. I will establish the role of gamma-secretase activity, and cleavage products, by concentrating on major substrates of gamma-secretase, which also play an important role in synaptic transmission: APP, EphB2 and N-cadherin.
This project will combine my expertise in molecular and cellular biology of the gamma-secretase with innovative imaging techniques and optophysiology developed in the host laboratory.
The results will provide original elements highlighting non-amyloid mechanisms in AD. Identifying the role of gamma-secretase cleavage products may for example open new avenues for therapeutic research.

Project coordinator


The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.



Help of the ANR 580,320 euros
Beginning and duration of the scientific project: October 2011 - 36 Months

Useful links

Explorez notre base de projets financés



ANR makes available its datasets on funded projects, click here to find more.

Sign up for the latest news:
Subscribe to our newsletter