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Luísa Lopes Lab

Neurobiology of Ageing & Disease

Our research primarily focuses on cognitive functions such as memory, learning, and aging. We aim at exploring how synaptic function influences brain plasticity and cognitive health, with a specific interest in understanding how disruptions in these systems (such as chronic stress and circadian dysfunction) contribute to age-related cognitive decline and dementia linked to neurodegenerative diseases.

By employing animal models and neurophysiology approaches we study the molecular mechanisms underlying these processes, investigating how specific neuronal proteins that control glutamatergic transmission impact on synaptic plasticity and how these interactions affect cognition upon aging.

Our upcoming work aims at implementing novel age-equivalent models using human-derived neurons, in order to translate these findings and address fundamental question in the field, such as the underlying synaptic mechanism of cognitive decline; to map the human synaptic signature of age-related cognitive impairment, with a focus on identifying factors leading to resilience versus vulnerability in cognitive aging.

Studying accelerated cognitive decline upon aging in human derived cholinergic neurons’

Agency: Fundação para a Ciência e Tecnologia (2022.03516.PTDC)

Unraveling the Mechanisms of Secondary Brain Injury in the Pathogenesis of Cerebral Venous Thrombosis

Agency: Fundação para a Ciência e Tecnologia (2023.13283.PEX)

‘Assessing aging of human neurons by direct induced neuronal (iN) conversion’

Agency: Fundação para a Ciência e Tecnologia | PTDC/MED-NEU/3890/2020)

‘Luminopsins in Parkinson’s disease stimulation’

Agency: “la Caixa” Impulse Innovation)

‘Insulin-degrading enzyme: a novel therapeutic target for Parkinson’s disease’

Agency: Michael J. Fox Foundation | MJFF-021400 | Role: co-PI

Horizon-MSCA-2021 ‘The health benefits of deuterium depletion on synaptic function, regional metabolism and behavior | Agency: European Commission| Role: Partner

Rajão-Saraiva J, Temido-Ferreira M, Coelho JE, Ribera A, Moreno S, Willem M, Marie H, Lopes LV, Pousinha PA (2023) Age-dependent NMDA receptor function is regulated by the amyloid precursor protein. Aging Cell. DOI: 10.1111/acel.13778.
We describe how the APP amyloidogenic-derived C-terminal fragments contribute to aberrant GluN2B-NMDAR currents in aging, which highlights the importance of keeping APP processing under tight control to ensure the normal functioning of glutamatergic synapses. This link between age-related changes in NMDA receptor activity and APP function may have implications for understanding age-related cognitive decline.

Temido-Ferreira M, Ferreira DG, Batalha VL, Marques-Morgado I, Coelho JE, Pereira P, Gomes R, Pinto A, Carvalho S, Canas PM, Cuvelier L, Buée-Scherrer V, Faivre E, Baqi Y, Müller CE, Pimentel J, Schiffmann SN, Buée L, Bader M, Outeiro TF, Blum D, Cunha RA, Marie H, Pousinha PA, Lopes LV (2020) Age-related shift in LTD is dependent on neuronal adenosine A2A receptors interplay with mGluR5 and NMDA receptors. Mol Psychiatry. DOI: 10.1038/s41380-018-0110-9.
We report an NMDA/mGluR5 and calcium overload in the glutamatergic synapses of memory-impaired aged rats that suggests a specific synaptic signature depending on cognitive trajectory in aging.

Batalha VL, Ferreira DG, Coelho JE, Valadas JS, Gomes R, Temido-Ferreira M, Shmidt T, Baqi Y, Buée L, Müller CE, Hamdane M, Outeiro TF, Bader M, Meijsing SH, Sadri-Vakili G, Blum D, Lopes LV (2016) The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function. Sci Rep. DOI: 10.1038/srep31493.
We show that inducing A2AR overexpression in an aging-like profile is sufficient to trigger HPA-axis dysfunction, namely loss of plasmatic corticosterone circadian oscillation, and promotes reduction of glucocorticoid receptor (GR) hippocampal levels. The synaptic plasticity and memory deficits triggered by GR in the hippocampus were rescued by anti-A2AR therapy.

Batalha VL, Pego JM, Fontinha BM, Costenla AR, Valadas JS, Baqi Y, Radjainia H, Müller CE, Sebastião AM, Lopes LV (2013) Adenosine A2A receptor blockade reverts hippocampal stress-induced deficits and restores corticosterone circadian oscillation. Mol Psychiatry. 18:320–331. DOI: 10.1038/mp.2012.8.
These results reveal the involvement of A(2A) receptors in stress-associated impairments and directly in the stress response system by showing that the dysfunction of the HPA-axis, as well as the long-lasting synaptic and behavioral effects of MS, can be reverted by targeting adenosine A(2A) receptors.

Ferreira DG, Temido-Ferreira M, Miranda HV, Batalha VL, Coelho JE, Szegö ÉM, Marques-Morgado I, Vaz SH, Rhee JS, Schmitz M, Zerr I, Outeiro TF, Lopes LV (2017) α-Synuclein interacts with PrPC to induce cognitive impairment through mGluR5 and NMDAR2B. Nat Neurosci. DOI: 10.1038/nn.4648.
We found that α-Synuclein, a protein implicated in Parkinson’s disease, interacts with PrPC, a cellular prion protein, resulting in cognitive impairment. This impairment occurs via the activation of two receptors: mGluR5 and NMDAR2B. These findings suggest a novel mechanism by which α-Synuclein pathology contributes to synaptic dysfunction and cognitive decline via mGluR5 and NMDAR2B signaling pathways in the hippocampus.

2022 – CEEC FCT position award (Coordinator)

2012 – Universidade de Lisboa /Caixa Geral de Depósitos award (Biomedicine)

2021 – Healthy Longevity Catalyst Award, National Academy Medicine (AMED)

2020 – Pfizer Basic Research Award

2019 – Interstellar Initiative Award 2019 Aging and longevity

(New York Academy of Sciences and Japan Agency for Medical Research and Development)

2018 – Mantero Belard Neuroscience Award (Santa Casa da Misericórdia de Lisboa)

2018 – Bial Research Award

2018 – CEEC FCT position award (Consolidator)

2017 – Universidade de Lisboa /Caixa Geral de Depósitos award (Menção Honrosa)

2013 – Investigator FCT award (Development), Fundação para a Ciência e Tecnologia, Portugal

2012 – Research award, EMBO