Our group investigates how genetic risk factors that affect endosomes contribute to late-onset Alzheimer’s disease (AD) by disrupting endocytic trafficking and synaptic function. We also examine how cellular aging affects neurons, thereby amplifying disease vulnerability.
We combine advanced quantitative microscopy, from live-cell to super-resolution imaging, with mechanistic studies in mouse cortical neurons, neuronal cell lines, and human neurons derived from induced pluripotent stem cells (hiPSCs). Using CRISPR-based gene editing, we introduce patient-specific mutations into healthy neurons to model late-onset AD under controlled genetic backgrounds.
By dissecting these early cellular mechanisms, we aim to identify druggable molecular pathways responsible for synaptic failure during a potentially reversible phase of the disease. Our work seeks to bridge the gap between cellular and molecular neuroscience and translational research, advancing precision models that can inform the development of targeted therapies for Alzheimer’s disease.
Projects
- 2024-2027 | Early detection of neurodegenerative diseases through the study of tau protein aggregates - Pep-SICO
Funding: La Caixa Research; Project Leader Ana Pina (ITQB)
Several neurodegenerative diseases involve tau protein accumulation, impairing brain function and causing cognitive decline. By 2050, 130 million people may be affected. Current diagnostics are symptom-based, hindering early detection. The project aims to develop Pep-SICO, a fluorescent tool for early diagnosis of tau-related diseases.
- 2026-2027 | Synapse Protection: A Novel Therapeutic Strategy for Alzheimer's Disease (2024.15725.PEX)
Funding: FCT; Principal investigator Cláudia Almeida
The limited success of amyloid-based therapies in Alzheimer’s disease (AD) highlights the need to target earlier disease mechanisms, particularly synaptic dysfunction in late-onset AD (LOAD). Genetic studies identify BIN1 as a major risk gene for endosomal trafficking, yet its synaptic role remains unclear. Our work revealed that BIN1 loss-of-function selectively impairs specific synapses in neurons, independently of amyloid pathology, and that an approved drug can rescue these deficits. The Dear-Synapse project translates these findings to human iPSC-derived neurons, combining gene editing, advanced microscopy, and neurophysiology to uncover druggable, synapse-protective mechanisms for BIN1-associated AD.
Publications
- Barata, M. A., Perdigão, C., Ramalho, J., Gomes, E. R., & Guimas Almeida, C. (2025). Alzheimer's genetic risk factor Bin1 controls synapse vesicle exo-endocytosis in inhibitory synapses. Cell reports, 44(8), 116005. https://doi.org/10.1016/j.celrep.2025.116005
- Mirfakhar, F. S., Castanheira, J., Domingues, R., Ramalho, J. S., & Guimas Almeida, C. (2024). The Alzheimer's Disease Risk Gene CD2AP Functions in Dendritic Spines by Remodeling F-Actin. The Journal of neuroscience : the official journal of the Society for Neuroscience, 44(48), e1734232024. https://doi.org/10.1523/JNEUROSCI.1734-23.2024
- Burrinha T, Cunha C, Hall MJ, Lopes-da-Silva M, Seabra MC, Guimas Almeida C. Deacidification of endolysosomes by neuronal aging drives synapse loss. Traffic. 2023 Aug;24(8):334-354.
https://onlinelibrary.wiley.com/doi/10.1111/tra.12889
- Burrinha, T., Martinsson, I., Gomes, R., Terrasso, A. P., Gouras, G. K., & Almeida, C. G. (2021). Upregulation of APP endocytosis by neuronal aging drives amyloid-dependent synapse loss. Journal of cell science, 134(9), jcs255752. https://doi.org/10.1242/jcs.255752
- Perdigão, C., Barata, M. A., Burrinha, T., & Guimas Almeida, C. (2021). Alzheimer's disease BIN1 coding variants increase intracellular Aβ levels by interfering with BACE1 recycling. The Journal of biological chemistry, 297(3), 101056. https://doi.org/10.1016/j.jbc.2021.101056
- Perdigão, C., Barata, M. A., Araújo, M. N., Mirfakhar, F. S., Castanheira, J., & Guimas Almeida, C. (2020). Intracellular Trafficking Mechanisms of Synaptic Dysfunction in Alzheimer's Disease. Frontiers in cellular neuroscience, 14, 72. https://doi.org/10.3389/fncel.2020.00072
- Guimas Almeida, C., Sadat Mirfakhar, F., Perdigão, C., & Burrinha, T. (2018). Impact of late-onset Alzheimer's genetic risk factors on beta-amyloid endocytic production. Cellular and molecular life sciences : CMLS, 75(14), 2577–2589. https://doi.org/10.1007/s00018-018-2825-9
- Ubelmann, F., Burrinha, T., Salavessa, L., Gomes, R., Ferreira, C., Moreno, N., & Guimas Almeida, C. (2017). Bin1 and CD2AP polarise the endocytic generation of beta-amyloid. EMBO reports, 18(1), 102–122. https://doi.org/10.15252/embr.201642738
Prizes and Awards
- 2025 – Jorge Castanheira Poster Award, NMS Research Symposium, Lisbon, Portugal
- 2025 – Ana Caulino, BRSA travel grant, BRSA Ageing Meeting 2025
- 2025 – Ana Caulino, BRSA Commercialization of Research competition award
- 2025 – Ana Caulino, SPN travel grant, XIX Meeting Portuguese Society for Neuroscience
- 2024 – Ana Caulino, Best Presentation Award, NMS PhD Students Retreat
- 2024 – Ana Caulino, SPN travel grant, FENS 2024
- 2024 – Ana Caulino, 1st prize, EUTOPIA Summer School
- 2024 – Guimas Almeida C, Conference Fellowship, Alzheimer’s Association International Conference (AAIC), Philadelphia, USA
- 2023 – Jorge Castanheira, IBRO Travel Grant, FENS Regional Meeting, Faro, Portugal
- 2022 – Guimas Almeida C (co-winner), 1st International Blended Learning Award – Health and Wellbeing
- 2022 – Jorge Castanheira, Travel Award, 8th European Synapse Meeting, Coimbra, Portugal
- 2021 – Jorge Castanheira, SPN Travel Award, Coimbra, Portugal
Employment / salary & other funding:
- 2022–2028 – Guimas Almeida C, Principal Investigator Salary (iNOVA4Health), FCT Stimulus for Scientific Employment
- 2019–2025 – Guimas Almeida C, FCT Scientific Stimulus Contract (CEEC 2017, cancelled 2022)
- 2018 – Guimas Almeida C, FLAD Travel Grant
- 2018 – Guimas Almeida C, SPN Travel Grant
- 2017 – Guimas Almeida C, Maratona da Saúde Neurodegenerative Diseases Award (Biogen)
- 2017 – Guimas Almeida C, Honorable Mention, Award Criostaminal/RTP 2016
- 2015 – Guimas Almeida C, NOVA/Santander-Totta Award for collaborative project in life sciences
- 2013–2018 – Starting Researcher Salary, “Investigador FCT”, FCT, Portugal.
Open Positions
Research Grant (BI), for the conduct of R&D activities by a graduate with a Master degree enrolled in a course non-leading to an academic degree - Ref. ª SAI/2025/08
There is an open call for applications for a Research Grant (BI), for the conduct of R&D activities by a graduate with a Master degree enrolled in a course non-leading to an academic degree, under reference SAI/2025/08 in the scope of the UID/04462: iNOVA4Health – Programme in Translational Medicine project, at the institution Faculdade de Ciências Médicas|NOVA Medical School (FCM|NMS) from Universidade NOVA de Lisboa (UNL), supported by income from the above mentioned project, financed by the Fundação para a Ciência e a Tecnologia, I.P.).
Field of study: Neurosciences
Link for EURAXESS: Notice SAI/2025/08
Research Grant (BI), for the conduct of R&D activities by a graduate with a Master - Ref. SF/2025/10
There is an open call for applications for a Research Grant (BI), for the conduct of R&D activities by a graduate with a Master degree to be enrolled in a course not-leading to an academic degree, under reference SF/2025/10 in the scope of the Pep-Sico (M3A0108) project, at the institution Faculdade de Ciências Médicas|NOVA Medical School (FCM|NMS) from Universidade NOVA de Lisboa (UNL), supported by income from the above mentioned project, financed by the La Caixa Foundation under the following conditions:
Field of study
Biomedicine
Link for EURAXESS: Notice SF/2025/10
Research Grant (BI), for the conduct of R&D activities by a graduate with a Bachelor degree enrolled in a Master degree or a course non-leading to an academic degree - Ref. ª SF/2025/19
There is an open call for applications for a Research Grant (BI), for the conduct of R&D activities by a graduate with a Bachelor (“Licenciatura”) degree enrolled in a Master degree or a course non-leading to an academic degree, under reference SF/2025/18 in the scope of the Pep-SICO project, at the institution Faculdade de Ciências Médicas|NOVA Medical School (FCM|NMS) from Universidade NOVA de Lisboa (UNL), supported by income from the above mentioned project, financed by La Caixa Foundation, under the following conditions:
Field of study: Biochemistry
Link for EURAXESS: Notice SF/2025/19
Colaborations
- José Ramalho - NOVA Medical School, Portugal
- Ira Milosevic - MIA, Germany
- Luísa Lopes - Instituto de Medicina Molecular João Lobo Antunes (iMM/GiMM), Portugal
- Edgar Gomes - Instituto de Medicina Molecular João Lobo Antunes (iMM/GiMM), Portugal
- Gunnar Gouras - U Lund, Sweden
- Agnieska Ribok-Wolf .- MDC, Germany
- Mireya Plass - IBIDELL, Spain
- Henrik Zetterberg - U Gotthenburg, Sweden
- Ilse Smolders - VUB, Belgium
- Sofia Ramos - U Lusófona