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Levetiracetam prevents Aβ42 production through SV2a-dependent modulation of App processing in Alzheimer’s disease models

Nalini R. Rao, Olivia DeGulis, Toshihiro Nomura, SeungEun Lee, Timothy J. Hark, Justin C. Dynes, Emily X. Dexter, Maciej Dulewicz, Junyue Ge, Arun Upadhyay, Eugenio F. Fornasiero, Robert Vassar, Jörg Hanrieder, Anis Contractor, Jeffrey N. Savas

Posted on: 11 January 2025 , updated on: 17 January 2025

Preprint posted on 28 October 2024

A promising therapeutic role for a synaptic vesicle binding drug in Alzheimer’s disease

Selected by Jawdat Sandakly

Background

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and progressive cognitive decline. Its main hallmarks include an abnormal accumulation of amyloid beta (Aβ) plaques and hyperphosphorylated tau neurofibrillary tangles. There is compelling evidence indicating that synaptic impairment correlates strongly with the cognitive deficits seen in AD.

Antiepileptic drugs have been heavily investigated to prevent neuronal hyperexcitability and slow down the progression of AD symptoms. Among these drugs, Levetiracetam (Lev) has been approved to be used in the treatment of a wide range of neurological conditions. Its exact mechanism of action remains unclear, but it is known to bind synaptic vesicle protein 2A (SV2A), an integral membrane protein responsible for trafficking neurotransmitters and facilitating their release into the synapse. Lev reduces plaque pathology, memory deficits and slows down cognitive decline. It has been shown that the synaptic vesicle cycle drives the release of Aβ from neurons and that oligomers of Aβ42, the 42 amino acid proteolytic product of APP, interact with proteins participating in regulating this cycle. With the inability of the currently FDA approved AD drugs to stop Aβ production, the authors aimed with this study to investigate the therapeutic mechanism of action of Lev in the modulation of Aβ accumulation.

 

Main findings adapted from the preprint

 

Key findings

Proteins with impaired degradation accumulate at presynaptic sites in an AD KI mouse model

In a previous study, the authors of this preprint determined that turnover of proteins associated with presynaptic terminals is impaired in two App KI mouse models that knock in App prior to the accumulation of plaques and during diseases progression. Here they determined by immunofluorescence assays that there is an accumulation of these proteins near the presynaptic sites.

 

Lev reduces amyloidogenic processing of APP

To test if Lev affects Aβ42, the authors overexpressed APP in vitro using lentiviral vectors expressing either full length human APP or mutated APP. Neurons overexpressing the latter had increased levels of the APP 𝛽-C-terminal fragment (𝛽-CTF). Incubation of these neurons with Lev resulted in a robust decrease of 𝛽-CTF and Aβ42 levels but not the full-length APP levels.

 

Lev corrects SV dynamics and increases the levels of APP on the cell surface

Using mass spectrometry, the authors next wanted to investigate how Lev alters the proteome of these neurons. Within the group of proteins significantly modulated by Lev, there was an overrepresentation of proteins associated with membranes and vesicles. To address how Lev impacts the dynamics of synaptic vesicle (SV) exocytosis and endocytosis, a live cell surface Syt1-luminal-657 antibody binding assay was performed; treatment with the drug significantly increased the abundance of Synaptotagmin 1, an integral membrane protein of the synaptic vesicle. Moreover, live cell labelling of the surface proteome using biotin followed by Western Blot showed that Lev significantly increased plasma membrane APP levels.

 

Lev treatment prevents Aβ42 production and minimizes synapse loss in vivo

To confirm the results in vivo, the authors treated an App KI mouse model (NL-F mice) with Lev and noted that the treated females exhibited significantly reduced Aβ42 levels. Proteomics analysis revealed many proteins associated with synaptic vesicle (SV) cycling had significantly reduced levels after Lev treatment.

Lev treatment of a transgenic AD mouse model also exhibiting synaptic loss (J20 mice) significantly reduced the amyloid pathology-induced cognitive defects and the excitatory synaptic transmission.

 

What I like about the preprint

This preprint paves the way for future investigations on Lev as a promising AD drug as it presents novel insights into Lev’s mechanism of action in synaptic vesicles and sheds light on the importance of synaptic plasticity in AD. What I found particularly interesting is that the authors used a model that recapitulates both the disease and synapse impairments at the same time to evaluate the efficiency of the drug in preventing synapse deterioration.

 

Future directions and questions for the authors

  • The effects seen on the treated neurons as well as the mass spectrometry results made me curious whether you will be conducting some analysis to evaluate and characterize the structure of the synaptic vesicles by electron microscopy or other imaging techniques.
  • In a recent study, it was shown that SV2A levels are normalized upon treatment with levetiracetam in Tg4510 mice. Are you planning on evaluating the prevention of Aβ42 production in different AD models in addition to the ones used in this preprint?

 

References

    • Thompson, J.C. et al. (2024) ‘Evaluating the efficacy of levetiracetam on non-cognitive symptoms and pathology in a tau mouse model’, Biomedicines, 12(12), p. 2891. doi:10.3390/biomedicines12122891.
    • Jordà‐Siquier, T. et al. (2022) ‘App accumulates with presynaptic proteins around amyloid plaques: A role for presynaptic mechanisms in alzheimer’s disease?’, Alzheimer’s & Dementia, 18(11), pp. 2099–2116. doi:10.1002/alz.12546.
    • Barthet, G. and Mulle, C. (2020) ‘Presynaptic failure in alzheimer’s disease’, Progress in Neurobiology, 194, p. 101801. doi:10.1016/j.pneurobio.2020.101801.
    • Karisetty, B.C. et al. (2020) ‘Amyloid-β peptide impact on synaptic function and neuroepigenetic gene control reveal new therapeutic strategies for alzheimer’s disease’, Frontiers in Molecular Neuroscience, 13. doi:10.3389/fnmol.2020.577622.
    • Cirrito, J.R. et al. (2008) ‘Endocytosis is required for synaptic activity-dependent release of amyloid-β in vivo’, Neuron, 58(1), pp. 42–51. doi:10.1016/j.neuron.2008.02.003.

Tags: alzheimer, amyloid-beta, synapse

doi: https://doi.org/10.1242/prelights.39416

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Author's response

Dr. Nalini Rao shared

  • That’s a great question! Yes, I think it would be very interesting to further investigate why targeting SV2A slows down synaptic vesicle (SV) cycling dynamics. EM could provide valuable insight into how the docking and release states of SVs are modulated by Lev treatment. In addition, our previous work found that AD KI mice have an elevated SV pool, so it would also be interesting
    to assess whether the effect of Lev on slowing SV cycling results in a rescued readily releasable pool of SVs.
  • This is certainly an important consideration. Going forward, we plan to focus more on understanding the relationship between SV2A and Syt1. In our previous study, we identified Syt1 as one of the top proteins with slowed turnover and increased abundance. In this manuscript, we observed that Lev treatment strongly reduced Syt1 abundance. These findings, along with previous reports highlighting the role of SV2A and Syt1 in SV cycling, we believe motivate a deeper dive into how Lev modulates this relationship.

 

 

 

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