Job ID: 118722

Project for potential PhD students working on an Alzheimer model

Position: Ph.D. Student

Deadline: 15 May 2024

Employment Start Date: 1 October 2024

Contract Length: 3 years

City: Paris

Country: France

Institution: Institut Pasteur

Department: Neuroscience

Description:

We are inviting applications from prospective PhD students to apply together for competitive funding. This funding comes from Paris-based Doctoral Schools after competitive evaluation. Prospective students should have first experience in two-photon imaging.

 

 

Role of nicotinic acetylcholine receptors in Alzheimer’s disease pathology and treatment

 

Background: Nicotinic acetylcholine receptors (nAChRs) are a main target of Alzheimer’s disease (AD) pathology, reviewed in Lombardo&Maskos (1). Here, we propose to study the early events of how amyloid beta peptide (Abeta), linked to AD, interferes with the function of the different classes of nAChRs.

nAChRs mediate the action of acetylcholine (ACh) in the brain, and respond to nicotine in smokers. They are implicated in a number of other diseases including Parkinson’s, schizophrenia, autism, multiple sclerosis, and of course nicotine addiction (2). A total of 16 genes are known, and many of them are expressed in the brain, like alpha2 to alpha7, and beta2 to beta4. They can form homopentamers composed of five alpha7 subunits, (alpha7)5, and heteropentamers, composed of different alpha and beta subunits, like the (alpha4)2(beta2)2alpha5 pentamer, described in our recent Nature Medicine paper (3).

nAChRs are expressed in different neuronal population in prefrontal cortex (PFC), which has been analysed extensively by our collaborator, Huib Mansvelder (4). In a submitted paper, we show that in upper PFC layers, 1 to 3, nAChRs are expressed on different kinds of interneurons, like parvalbumin (PV), somatostatin (SOM), and VIP. Over time, Abeta accumulation causes a differential inhibition of these GABAergic neurons, leading to global dis-inhibition of the pyramidal output neurons (5). This global increase in pyramidal neuron activity was the main phenotype in our original description of the AD mouse model we established (6).

 

Scientific question: We will focus here on the lower layers, 5 and 6, of PFC, which are the output layers, that control executive function in the animal. We will use our published approaches to express soluble Abeta using an adenoviral vector (AAV) injected locally by stereotactic procedures (6).

In these lower layers, nAChRs are also expressed on the major classes of pyramidal neurons, alpha7 in layer 5, and the (alpha4)2(beta2)2alpha5 subtype in pyramidal neurons of layer 6. We will adapt our Abeta expression to these lower layers, and study the function of the pyramidal neurons over time. We will use the GCaMP8 calcium indicator to specifically image the different neuronal classes using Cre driver lines that are already available in our animal facility. For layer 5, these are the Rbp4-Cre (7), and for layer 6, Syt6-Cre (8) and Drd1-Cre (9). The local interneurons will be imaged in PV-Cre, SOM-Cre and VIP-Cre drivers as published by us before (3).

Our work in upper layers highlights a special role of alpha5 containing nAChRs, being partially “resistant” to block by soluble Abeta. We have submitted a DI (Déclaration d’invention) suggesting medication to normalise network activity in early stage AD. This is an important question, as 35% of the European population carry a coding polymorphism, rs16969968, in alpha5. We have worked extensively on the consequences of this single amino acid change, and have summarised the main findings recently (10).

As before, we will therefore also analyse “humanised” knock-in mice expressing a coding polymorphism rs16969968 in alpha5 (3). The outcome will establish whether carriers of this mutation, 35% of the European population, are more, or less, affected by early AD-like pathology.

As part of our ongoing R&D contract with a major pharmaceutical company, we will then test molecules destined to target alpha5 containing receptors, and follow their potentially protective effect over time. These are “positive allosteric modulators” (PAMs) (11) and agonists of alpha5 containing receptors, as outlined in the discussion of our recent review (10).

 

References

  1. Lombardo, S. and Maskos, U. (2015) Neuropharmacology 96, 255–262 2. Changeux, J. P. (2010) Nat Rev Neurosci 11, 389–401 3. Koukouli, F., et al (2017) Nat. Med. 23, 347–354 4. Bloem, B., et al (2014) Front. Neural Circuits 8, doi: 10.3389/fncir.2014.00017 5. Koukouli, F., et al (2024) Nicotinic receptors mediate network dysfunction in early Alzheimer’s disease. submitted 6. Koukouli, F., et al (2016) Aging (Albany. NY). 8, 3430–3449 7.   de Vries, S. E. J., et al (2020) Nat. Neurosci. 23, 138–151 8. Nakayama, H., et al (2018) J. Neurosci. 38, 3537–17 9. Lemberger, T., et al. BMC Neurosci. 8, doi:10.1186/1471-2202-8-4 10. Maskos, U. (2020) J. Neurochem. DOI: 10.1111/jnc.14989 11. Taly, A., et al. (2009) Nat Rev Drug Discov 8, 733–750