Ferrer, I. (Isidro)
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- Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice(Elsevier, 2005) Ortiz, L. (Lourdes); Gomez-Isla, T. (Teresa); Avila, J. (Jesús); Perez-Mediavilla, L.A. (Luis Alberto); Ramos, P. (Pilar); Catena, S. (Silvia); Cabodevilla, F. (Felipe); Perez, M. (Mar); Samaranch, L. (Lluis); Ribe, E. (Elena M.); Ferrer, I. (Isidro); Nieto, M. (María); Puig, B. (Berta); Moran, M.A. (María Asunción); Cuadrado-Tejedor, M. (Mar); Sesma, T. (Teresa); Gich, I. (Ignasi); Sanchez, B. (Belén); Lim, F. (Filip)Even though the idea that amyloid beta peptide accumulation is the primary event in the pathogenesis of Alzheimer's disease has become the leading hypothesis, the causal link between aberrant amyloid precursor protein processing and tau alterations in this type of dementia remains controversial. We further investigated the role of beta-amyloid production/deposition in tau pathology and neuronal cell death in the mouse brain by crossing Tg2576 and VLW lines expressing human mutant amyloid precursor protein and human mutant tau, respectively. The resulting double transgenic mice showed enhanced amyloid deposition accompanied by neurofibrillary degeneration and overt neuronal loss in selectively vulnerable brain limbic areas. These findings challenge the idea that tau pathology in Alzheimer's disease is merely a downstream effect of amyloid production/deposition and suggest that reciprocal interactions between beta-amyloid and tau alterations may take place in vivo.
- Early-onset molecular derangements in the olfactory bulb of Tg2576 mice: Novel insights into the stress-responsive olfactory kinase dynamics in alzheimer’s disease(Frontiers Media SA, 2019) Perez-Mediavilla, L.A. (Luis Alberto); Palomino, M. (Maialen); González-Morales, A. (Andrea); Ferrer, I. (Isidro); Fernandez-Irigoyen, J. (Joaquín); Gómez-Ochoa, M. (Marta); Zelaya, M.V. (María Victoria); Lachén-Montes, M. (Mercedes); Santamaria, E. (Enrique); Ausin, K. (Karina)The olfactory bulb (OB) is the first processing station in the olfactory pathway. Despite smell impairment, which is considered an early event in Alzheimer’s disease (AD), little is known about the initial molecular disturbances that accompany the AD development at olfactory level. We have interrogated the time-dependent OB molecular landscape in Tg2576 AD mice prior to the appearance of neuropathological amyloid plaques (2-, and 6-month-old), using combinatorial omics analysis. The metabolic modulation induced by overproduction of human mutated amyloid precursor protein (APP) clearly differs between both time points. Besides the progressive perturbation of the APP interactome, functional network analysis unveiled an inverse regulation of downstream extracellular signal-regulated kinase (ERK1/2), and p38 mitogen-activated protein kinase (MAPK) routes in 2-month-old Tg2576 mice with respect to wild-type (WT) mice. In contrast, Akt and MAPK kinase 4 (SEK1)/ stress-activated protein kinase (SAPK) axis were parallel activated in the OB of 6-months-old-Tg2576 mice. Furthermore, a survival kinome profiling performed during the aging process (2-, 6-, and 18-month-old) revealed that olfactory APP overexpression leads to changes in the activation dynamics of protein kinase A (PKA), and SEK1/MKK4-SAPK/JNK between 6 and 18 months of age, when memory deficits appear and AD pathology is well established in transgenic mice. Interestingly, both olfactory pathways were differentially activated in a stage-dependent manner in human sporadic AD subjects with different neuropathological grading. Taken together, our data reflect the early impact of mutated APP on the OB molecular homeostasis, highlighting the progressive modulation of specific signaling pathways during the olfactory amyloidogenic pathology
- Increased sensitivity to MPTP in human alpha-synuclein A30P transgenic mice(Elsevier, 2006) Gomez-Isla, T. (Teresa); Dalfo, E. (Esther); Ramirez, M.J. (María Javier); Catena, S. (Silvia); Cabodevilla, F. (Felipe); Ribe, E. (Elena M.); Ferrer, I. (Isidro); Nieto, M. (María); Gil-Bea, F.J. (Francisco J.); Cuadrado-Tejedor, M. (Mar); Sesma, T. (Teresa); Sanchez, B. (Belén)In addition to genetic factors, environmental factors have long been suspected to contribute to the pathogenesis of Parkinson's disease (PD). We investigated the possible interaction between genetic factors and neurotoxins by testing whether alpha-synuclein A30P Tg5093 transgenic mice show increased sensitivity to secondary toxic insults like 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or rotenone. While sensitivity to chronic treatment with rotenone was not enhanced in the Tg5093 line, chronic treatment with 80 or 150 mg/kg MPTP resulted in increased deterioration of the nigrostriatal dopaminergic system as assessed by quantitation of nigral tyrosine hydroxylase (TH) positive neurons and striatal dopamine (DA) levels in Tg5093 mice when compared to non-transgenic littermate controls. Thus, the results of this study demonstrate a role for the overexpression of mutant human alpha-synuclein A30P in increased vulnerability of DA neurons to MPTP.
- Immunotherapy for neurological diseases(Elsevier, 2008) Rivest, S. (Serge); Schwartz, M. (Michal); Avila, J. (Jesús); Khoury, S.J. (Samia J.); Obeso, J.A. (José A.); Moreno, B. (Beatriz); Martino, G. (Gianvito); Acarin, L. (Laia); Ferrer, I. (Isidro); Villoslada, P. (Pablo); McGeer, P. (Patrick); Appel, S. (Stanley); Montalban, X. (Xavier); Melero, I. (Ignacio); Uccelli, A. (Antonio); Delgado, M. (Mario); Pablos, J.L. (José L.)The burden of neurological diseases in western societies has accentuated the need to develop effective therapies to stop the progression of chronic neurological diseases. Recent discoveries regarding the role of the immune system in brain damage coupled with the development of new technologies to manipulate the immune response make immunotherapies an attractive possibility to treat neurological diseases. The wide repertoire of immune responses and the possibility to engineer such responses, as well as their capacity to promote tissue repair, indicates that immunotherapy might offer benefits in the treatment of neurological diseases, similar to the benefits that are being associated with the treatment of cancer and autoimmune diseases. However, before applying such strategies to patients it is necessary to better understand the pathologies to be targeted, as well as how individual subjects may respond to immunotherapies, either in isolation or in combination. Due to the powerful effects of the immune system, one priority is to avoid tissue damage due to the activity of the immune system, particularly considering that the nervous system does not tolerate even the smallest amount of tissue damage.
- Smelling the dark proteome: Functional characterization of PITH domain-containing protein 1 (C1orf128) in olfactory metabolism(ACS Publications, 2020) Elortza, F. (Felix); Perez-Mediavilla, L.A. (Luis Alberto); Azkargorta, M. (Mikel); Torre, R. (Rafael) de la; Ferrer, I. (Isidro); Fernandez-Irigoyen, J. (Joaquín); Ohigashi, I. (Izumi); Iloro, I. (Ibon); Kondo, H. (Hiroyuki); Lachén-Montes, M. (Mercedes); Mendizuri, N. (Naroa); Santamaria, E. (Enrique); Ausin, K. (Karina); Robledo-Ramón, P. (Patricia)The Human Proteome Project (HPP) consortium aims to functionally characterize the dark proteome. On the basis of the relevance of olfaction in early neurodegeneration, we have analyzed the dark proteome using data mining in public resources and omics data sets derived from the human olfactory system. Multiple dark proteins localize at synaptic terminals and may be involved in amyloidopathies such as Alzheimer’s disease (AD). We have characterized the dark PITH domain-containing protein 1 (PITHD1) in olfactory metabolism using bioinformatics, proteomics, in vitro and in vivo studies, and neuropathology. PITHD1–/– mice exhibit olfactory bulb (OB) proteome changes related to synaptic transmission, cognition, and memory. OB PITHD1 expression increases with age in wild-type (WT) mice and decreases in Tg2576 AD mice at late stages. The analysis across 6 neurological disorders reveals that olfactory tract (OT) PITHD1 is specifically upregulated in human AD. Stimulation of olfactory neuroepithelial (ON) cells with PITHD1 alters the ON phosphoproteome, modifies the proliferation rate, and induces a pro-inflammatory phenotype. This workflow applied by the Spanish C-HPP and Human Brain Proteome Project (HBPP) teams across the ON-OB-OT axis can be adapted as a guidance to decipher functional features of dark proteins. Data are available via ProteomeXchange with identifiers PXD018784 and PXD021634.