Brain-derived extracellular vesicle proteomics reveals neuroprotection induced by the ARB candesartan in Parkinson’s disease patients Laura Camacho-Meño, Carmen M. Labandeira, Susana B. Bravo, Mateo V. Torres, Helena Bejr-Kasem, Angela Molina-Crespo, Mercedes Atienza, Jose L. Lanciego, Jose L. Cantero, Jaime Kulisevsky, Jose Luis Labandeira-Garcia, Ana I. Rodriguez-Perez Npj Parkinson S Disease, 2026 In models of Parkinson's disease (PD), angiotensin-II type-1 receptor (AT1) blockers (ARBs) mitigated the vulnerability of dopaminergic neurons, which aligns with recent transcriptomic studies of human brains showing increased susceptibility of dopaminergic neurons with high AGTR1 expression, and with epidemiological data indicating an ARB-related reduction in PD incidence. However, there is no experimental evidence in PD patients. Using a minimally invasive strategy based on the isolation of blood extracellular vesicles (EVs) from neuronal, microglial/macrophage, astrocytic, and oligodendrocytic origin, we report proteomic profiles from patients treated with the ARB candesartan. Candesartan treatment led to the differential expression of key proteins involved in PD pathogenesis: 46 in neuron-derived EVs, 48 in microglia/macrophage-derived EVs, 22 in astrocyte-derived EVs, and 92 in oligodendrocyte-derived EVs. Our findings provide the first direct molecular evidence of neuroprotective mechanisms triggered by ARBs in PD patients and support the rationale for larger clinical trials on ARB repurposing.
Associations of plasma phosphorylated tau217 with cognitive impairment and brain microstructural alterations in Alzheimer's disease Miguel Ángel Rivas‐Fernández, Sara Basanta‐Torres, Mónica Lindín, Montserrat Zurrón, Fernando Díaz, Arturo Xosé Pereiro, Cristina Lojo‐Seoane, Ana Isabel Rodríguez‐Pérez, José Luis Labandeira, Santiago Galdo‐Álvarez Alzheimer S and Dementia Diagnosis Assessment and Disease Monitoring, 2026 Introduction Plasma phosphorylated tau217 (p‐tau217) is a promising biomarker for Alzheimer's disease (AD) risk detection. Its relationship with brain microstructure and cognitive impairment remains unclear. Multi‐component T2‐relaxometry is an MRI technique sensitive to myelin content, axonal degeneration, and neuroinflammation. Methods A total of 229 participants classified by p‐tau217 levels into p‐tau217– ( n = 176), p‐tau217+ ( n = 26), and intermediate ( n = 27) underwent neuropsychological testing and MRI. Voxel‐wise general linear models controlling for age, sex, education, apolipoprotein E ( APOE , and white matter lesions were performed for total water content (TWC), myelin water fraction (MWF), intra‐/extracellular water fraction (IEWF), geometric mean of intra‐/extracellular water (T2 IE ), and free/quasi‐free water fraction (FQFWF). Results The p‐tau217+ participants showed poorer cognition, increases in FQFWF and TWC, and reductions in IEWF and T2 IE across cortical and subcortical regions and white matter tracts. Discussion High p‐tau217 level associates with brain microstructure alterations and poorer cognition, supporting it as a biomarker of AD‐related neuropathology and the utility of T2‐relaxometry for detecting tissue integrity.
Delivery of monoclonal antibodies to the brain: the impact of nanocarrier structure Laura Pineiro-Alonso, Inés Rubio-Prego, Ana M. López-Estévez, Pablo Garrido-Gil, Rita Valenzuela, José L. Labandeira-García, Pablo Aguiar, Ana I. Rodríguez-Pérez, María J. Alonso Drug Delivery and Translational Research, 2026 Monoclonal antibodies (mAbs) are promising therapeutic agents for neurological disorders due to their high specificity. However, their clinical application is significantly hindered by their poor transport across the blood-brain barrier (BBB) and their limited diffusion within the brain parenchyma. While significant efforts have been oriented to tackle the first barrier, the challenge of efficient brain diffusion remains largely underexplored. To address this, we have developed and evaluated two structurally distinct nanosystems for mAb delivery to the brain: PEGylated polyglutamic acid nanocapsules (PGA-PEG NCs) and PGAC14-based nanoassemblies (PGAC14 NAs). Both formulations encapsulated efficiently the model mAb bevacizumab (BVZ) while they exhibited different physicochemical properties. Namely, PGA-PEG NCs displayed a size of 80 nm and a neutral zeta potential, whereas PGAC14 NAs featured an ultra-small size of 40 nm and a negative surface charge. After assessing their diffusion capacity using immunofluorescence, we concluded that PGAC14 NAs exhibited the highest brain diffusion together with a favorable neuroinflammatory profile. This was likely driven by their small size and negative charge, along with a selective ability to interact with and deliver BVZ intracellularly to neuronal cells upon intraparenchymal administration. These findings provide key insights into optimizing nanocarrier design for improved mAb delivery to the brain.
Plasma and neurostructural biomarkers in the clinical-biological characterization of early stages of the Alzheimer's disease continuum: findings from the Compostela Aging Study Montserrat Zurrón, Arturo Xosé Pereiro, Ana Isabel Rodriguez-Perez, Santiago Galdo-Álvarez, Juan José Ansede, Cristina Lojo-Seoane, Mónica Lindín, David Facal, Miguel Ángel Rivas-Fernández, María Campos-Magdaleno, Ángel Carracedo, José Luis Labandeira-Garcia, Fernando Díaz Journal of Prevention of Alzheimer S Disease, 2026 Recent technical advances in peripheral blood analysis have enabled precise quantification of Alzheimer´s Disease (AD) biomarkers in the early stages of the AD continuum, in an economical, non-invasive and safe manner. The main objective of this study was to contribute to the clinical-biological characterization of the initial stages of cognitive impairment by measurement of blood and neurostructural AD biomarkers in groups of participants classified according to their cognitive clinical phenotype. Plasma concentrations of p-tau217, p-tau181, total tau, neurofilament light chain and amyloid-β 42/40 ratio biomarkers were measured along with APOE gene variants, hippocampal volume and cortical thickness of the AD signature regions. The cohort of 329 participants included Cognitively Unimpaired (CU), Subjective Cognitive Decline (SCD), single-domain amnestic Mild Cognitive Impairment (sd-aMCI), multidomain aMCI (md-aMCI), and single-domain non-amnestic MCI (sd-naMCI) groups. P-tau217 concentrations were significantly higher in the md-aMCI and sd-aMCI groups than in the CU, SCD and sd-naMCI groups. P-tau181 concentrations were significantly higher in md-aMCI group than in CU, SCD and sd-naMCI groups. Hippocampal volume and AD signature cortical thickness were significantly lower in the md-aMCI group than in the CU, SCD and sd-naMCI groups. No across group differences were found in the distribution of carriers/non-carriers of APOE-ε4. Mediation analysis revealed that hippocampal volume and AD signature cortical thickness mediated the relationship between p-tau217 and p-tau181 levels and cognitive performance. Sd-aMCI and md-aMCI represent two distinct and sequential clinical-biological stages of the AD continuum. Conversely, sd-naMCI does not appear to be associated with AD pathology. Finally, the SCD group does not seem to display a higher risk of progression along the AD continuum than the CU group.
Renin–Angiotensin System Autoantibody Network in Parkinson’s Disease Patients Carmen M. Labandeira, Laura Camacho-Meño, Paula Aracil-Pastor, Juan A. Suárez-Quintanilla, Jose L. Labandeira-García, Ana I. Rodríguez-Pérez Antioxidants, 2025 The tissue renin–angiotensin system (RAS) is a regulator of oxidative and inflammatory homeostasis by balancing its pro-oxidative/pro-inflammatory axis (angiotensin II, AngII, and AngII type-1 receptor, AT1) and its anti-oxidative/anti-inflammatory axis (AngII/AT2 and ACE2/Ang1-7/Mas receptors). An RAS dysregulation contributes to diseases, including Parkinson’s disease (PD). Immune mechanisms are involved in PD. An increase in levels of pro-oxidative/pro-inflammatory autoantibodies for AT1 (AT1-AAs) and ACE2 (ACE2-AAs) has been recently observed in PD. However, it is not known whether dysregulation of autoantibodies for AT2, MasR, and the correlations among different RAS-AAs occurs in PD. In 106 controls and 117 PD patients, we used enzyme-linked immunosorbent assays to determine correlations among serum RAS-AAs, and among RAS-AAs and pro-inflammatory cytokines and 27-hydroxycholesterol. PD patients showed an increase in MasR-AAs, and a more interconnected cluster of correlations among RAS-AAs (AT1-AA, AT2-AA, MasR-AA, ACE2-AA), changes in RAS-AA networks with sex and age, and differences in networks between RAS-AAs and major PD-related pro-inflammatory cytokines and 27-hydroxycholesterol. The association between AT1-AAs and PD remained significant even after adjustment for age and other variables. This study reveals a disease-specific network of RAS autoantibodies in PD that links immune and oxidative pathways and identifies new biomarker patterns and potential therapeutic targets.
Fasudil inhibits α-synuclein aggregation through ROCK-inhibition-mediated mechanisms Lucia Lage, A. Rodriguez-Perez, J. Labandeira-García, Antonio Dominguez-Meijide Neurotherapeutics, 2025 ROCK inhibitors such as fasudil protected against dopaminergic degeneration and other neurodegenerative processes in several experimental models through inhibition of neuroinflammation and activation of survival signaling pathways, and clinical trials have been initiated. More recently, fasudil has been suggested to inhibit α-synuclein aggregation. However, this is controversial, particularly if it is a consequence of direct binding of the fasudil molecule to α-synuclein. We studied the mechanisms involved in the effects of fasudil on α-synuclein aggregation using the α-synuclein-T/V5-synphilin-1 model. Molecule-molecule interactions were studied using real time quaking inducing conversion (RT-QuiC). Fasudil decreased the number of cells with inclusions and the size of inclusions in dopaminergic neurons and glial cells, and inhibited α-synuclein aggregation and microglial endocytosis of aggregates. These changes were not due to changes in α-synuclein protein expression or phosphorylation and were related to ROCK inhibition rather than direct interaction with α-synuclein, as confirmed with a second ROCK inhibitor (Y27632) and ROCK gene silencing. We observed that ROCK inhibition downregulates several factors that are known to promote α-synuclein aggregation such as NADPH-oxidase-derived oxidative stress, intracellular calcium increase, and α-synuclein endocytosis, and promotes autophagy. The present results support that fasudil is a useful drug against Parkinson's disease progression. In addition to other reported neuroprotective properties, fasudil inhibits α-synuclein aggregation and microglial endocytosis of aggregates, which enhances the microglial inflammatory response. The effects of fasudil are mostly related to ROCK inhibition, which we have shown using two structurally different ROCK inhibitors and knockdown data, and further supported by using RT-QuiC.
Serum angiotensin type-1 receptor autoantibodies and neurofilament light chain as markers of neuroaxonal damage in post-COVID patients Ana I. Rodriguez-Perez, Gemma Serrano-Heras, Carmen M. Labandeira, Laura Camacho-Meño, Beatriz Castro-Robles, Juan A. Suarez-Quintanilla, Mónica Muñoz-López, Pepa Piqueras-Landete, María J. Guerra, Tomas Segura, José L. Labandeira-Garcia Frontiers in Immunology, 2025 IntroductionDysregulation of autoimmune responses and the presence of autoantibodies (AA), particularly those related to the renin-angiotensin system (RAS), have been implicated in the acute phase of COVID-19, and persistent dysregulation of brain RAS by RAS-related autoantibodies may also contribute to neurological symptoms of post-COVID. MethodsWe analyzed levels of serum and CSF RAS AA in post-COVID patients with neurological symptoms, individuals who have fully recovered from COVID-19 (after-COVID controls), and uninfected individuals, and their possible correlations with the serum marker of neuroaxonal damage neurofilament light chain (NfL) and the degrees of cognitive deficit. ResultsBoth in serum and CSF, levels of AA agonists of the pro-inflammatory angiotensin II type 1 receptors (AT1-AA) were significantly elevated in this cohort of neurological post-COVID patients compared to both uninfected and after-COVID controls and correlated with serum levels of NfL. Changes in serum and CSF levels of AA promoting the RAS anti-inflammatory axis (upregulation of AA agonists of AT2 and Mas receptors, downregulation of AA antagonists of ACE2) suggest upregulation of the RAS compensatory response in this cohort of neurological post-COVID patients. Post-COVID patients with more pronounced cognitive impairment exhibited significantly higher CSF levels of MasR-AA and a trend toward elevated AT2-AA. Persistent brain RAS dysregulation, particularly persistent increase in AT1-AA, and its correlation with neuroaxonal damage markers and cognitive impairment, may play a significant role in neurological symptoms associated with post-COVID. Serum levels of NfL and AT1-AA may be interesting biomarkers for the early identification of CNS involvement in patients with neurological symptoms and a history of COVID-19. However, post-COVID is a highly heterogeneous entity and may result from various underlying mechanisms. The present study includes a cohort, which may differ from other cohorts with different clinical profiles, which may show different results on NfLs and CSF RAS autoantibodies, particularly AT1-AA.ConclusionThese findings highlight the potential of targeting AT1 receptors as a therapeutic strategy for mitigating cognitive deficits in post-COVID patients showing upregulated AT1-AA levels.
The role of the brain renin-angiotensin system in Parkinson´s disease Jose Luis Labandeira-Garcia, Carmen M. Labandeira, Maria J. Guerra, Ana I. Rodriguez-Perez Translational Neurodegeneration, 2024 The renin-angiotensin system (RAS) was classically considered a circulating hormonal system that regulates blood pressure. However, different tissues and organs, including the brain, have a local paracrine RAS. Mutual regulation between the dopaminergic system and RAS has been observed in several tissues. Dysregulation of these interactions leads to renal and cardiovascular diseases, as well as progression of dopaminergic neuron degeneration in a major brain center of dopamine/angiotensin interaction such as the nigrostriatal system. A decrease in the dopaminergic function induces upregulation of the angiotensin type-1 (AT1) receptor activity, leading to recovery of dopamine levels. However, AT1 receptor overactivity in dopaminergic neurons and microglial cells upregulates the cellular NADPH-oxidase-superoxide axis and Ca2+ release, which mediate several key events in oxidative stress, neuroinflammation, and α-synuclein aggregation, involved in Parkinson's disease (PD) pathogenesis. An intraneuronal antioxidative/anti-inflammatory RAS counteracts the effects of the pro-oxidative AT1 receptor overactivity. Consistent with this, an imbalance in RAS activity towards the pro-oxidative/pro-inflammatory AT1 receptor axis has been observed in the substantia nigra and striatum of several animal models of high vulnerability to dopaminergic degeneration. Interestingly, autoantibodies against angiotensin-converting enzyme 2 and AT1 receptors are increased in PD models and PD patients and contribute to blood–brain barrier (BBB) dysregulation and nigrostriatal pro-inflammatory RAS upregulation. Therapeutic strategies addressed to the modulation of brain RAS, by AT1 receptor blockers (ARBs) and/or activation of the antioxidative axis (AT2, Mas receptors), may be neuroprotective for individuals with a high risk of developing PD or in prodromal stages of PD to reduce progression of the disease.
Angiotensin type 1 receptor activation promotes neuronal and glial alpha-synuclein aggregation and transmission Lucia Lage, A. Rodriguez-Perez, B. Villar-Cheda, J. Labandeira-García, Antonio Dominguez-Meijide Npj Parkinson S Disease, 2024 The brain renin-angiotensin system (RAS) has been related to dopaminergic degeneration, and high expression of the angiotensin II (AngII) type 1 receptor (AT1) gene is a marker of the most vulnerable neurons in humans. However, it is unknown whether AngII/AT1 overactivation affects α-synuclein aggregation and transmission. In vitro, AngII/AT1 activation increased α-synuclein aggregation in dopaminergic neurons and microglial cells, which was related to AngII-induced NADPH-oxidase activation and intracellular calcium raising. In mice, AngII/AT1 activation was involved in MPTP-induced increase in α-synuclein expression and aggregation, as they significantly decreased in mice treated with the AT1 blocker telmisartan and AT1 knockout mice. Cell co-cultures (transwells) revealed strong transmission of α-synuclein from dopaminergic neurons to astrocytes and microglia. AngII induced a higher α-synuclein uptake by microglial cells and an increase in the transfer of α-synuclein among astroglial cells. However, AngII did not increase the release of α-synuclein by neurons. The results further support brain RAS dysregulation as a major mechanism for the progression of Parkinson's disease, and AT1 inhibition and RAS modulation as therapeutic targets.
Biodistribution and pharmacokinetics of [89Zr]-anti-VEGF mAbs using PET in glioblastoma rat models Lara García-Varela, Jessica Codesido, Alberto Perez-Pedrosa, María Muñoz-González, Emma Ramos-Docampo, David Rey-Bretal, Xurxo García-Otero, Noemí Gómez-Lado, Angela Turrero, Daniel Beiroa, Ana Isabel Rodríguez-Perez, Anxo Vidal, Anxo Fernández-Ferreiro, Virginia Pubul, Pablo Aguiar International Journal of Pharmaceutics, 2024
Inflammatory bowel disease induces pathological α-synuclein aggregation in the human gut and brain Ana M. Espinosa‐Oliva, Rocío Ruiz, Manuel Sarmiento Soto, Antonio Boza‐Serrano, Ana I. Rodriguez‐Perez, María A. Roca‐Ceballos, Juan García‐Revilla, Marti Santiago, Sébastien Serres, Vasiliki Economopoulus, Ana E. Carvajal, María D. Vázquez‐Carretero, Pablo García‐Miranda, Oxana Klementieva, María J. Oliva‐Martín, Tomas Deierborg, Eloy Rivas, Nicola R. Sibson, José L. Labandeira‐García, Alberto Machado, María J. Peral, Antonio J. Herrera, José L. Venero, Rocío M. de Pablos Neuropathology and Applied Neurobiology, 2024
Angiotensin type-1 receptor and ACE2 autoantibodies in Parkinson´s disease Carmen M. Labandeira, Maria A. Pedrosa, Aloia Quijano, Rita Valenzuela, Pablo Garrido-Gil, Mariña Sanchez-Andrade, Juan A. Suarez-Quintanilla, Ana I. Rodriguez-Perez, Jose L. Labandeira-Garcia Npj Parkinson S Disease, 2022
An ACE2/Mas-related receptor MrgE axis in dopaminergic neuron mitochondria Rita Valenzuela, Ana I. Rodriguez-Perez, Maria A. Costa-Besada, Rafael Rivas-Santisteban, Pablo Garrido-Gil, Andrea Lopez-Lopez, Gemma Navarro, Jose L. Lanciego, Rafael Franco, Jose L. Labandeira-Garcia Redox Biology, 2021
Insulin-like growth factor-1 and neuroinflammation Jose L. Labandeira-Garcia, Maria A. Costa-Besada, Carmen M. Labandeira, Begoña Villar-Cheda, Ana I. Rodríguez-Perez Frontiers in Aging Neuroscience, 2017
