Biology subjects

Lanciego, J. L.

Publications and source records attributed to Lanciego, J. L..

5 recordsLinked to original sources

bioRxiv2025

sKL/mKL Transcript Ratio and Protein Localization Define a Species- and Region-Specific Klotho Signature in the CNS and AD Progression

-Klotho is a multifunctional protein widely recognized for its anti-aging and neuroprotective properties. This study investigates the expression and localization of the secreted Klotho (s-KL) isoform in the human brain and its potential role in Alzheimers disease. Using RT-qPCR, we observed that the s-KL transcript predominates over the membrane-bound KL (m-KL) in multiple brain regions, a pattern consistent in macaques and lemurs. Immunohistochemistry and immunoprecipitation assays confirmed the presence of the s-KL protein in human and mouse brain parenchyma, revealing species-specific cellular localization. In human cerebrospinal fluid (CSF), s-KL constitutes [~]28% of total KL, with levels significantly reduced in mild dementia-AD patients. These findings underscore s-KLs potential neuroprotective role and highlight its differential regulation and expression during AD progression.

neuroscience↗

bioRxiv2025

Introducing PIGMO, a novel PIGmented MOuse model of Parkinson's disease (V1)

There is a pressing need for the development, characterization, and standardization of animal models of Parkinsons disease (PD) that properly mimic the cardinal features of this disorder, comprising both the motor phenotype and neuropathological signatures. In the past few years, animal modeling has moved from neurotoxin-based approaches toward viral vectors carrying a given genetic payload of interest. Here, to induce pigmentation of the mouse brain upon systemic delivery, we took advantage of a modified adeno-associated viral vector capsid engineered to bypass the blood-brain barrier and coding for the human tyrosinase gene (AAV9-P31-hTyr). Obtained results revealed an ongoing pigmentation of catecholaminergic centers related to the pathophysiology of PD, such as the substantia nigra pars compacta, ventral tegmental area, and locus coeruleus. Moreover, pigmented dopaminergic neurons exhibited Lewy body-like intracytoplasmic inclusions, a progressive nigrostriatal degeneration, and a time-dependent PD motor phenotype. The bilateral pigmented mouse model of PD generated this way is highly reproducible, does not require stereotaxic surgery for viral vector deliveries, and opens unprecedented possibilities for preclinical testing of therapeutic candidates designed to reduce disease progression rates.

neuroscience↗

bioRxiv2024

Involvement of the cellular prion protein in seeding and spreading of sarkosyl-derived fractions of Alzheimer's disease in Prnp mutant mice and in the P301S transgenic tauopathy mice model

The natural cellular prion protein is known to play several roles during development and adult brain. Far from its pathological roles in prionopathies, the non-pathogenic cellular prion protein has been described as a receptor for several amyloid in oligomeric and prefibrillar forms. For some amyloids, specific domains of the protein play a crucial role in modulating amyloids cellular uptake and seeding properties. In most studies, the functions and the role of putative amyloid receptors have been analyzed by using brain extracts derived from human neurodegenerative patients. Another strategy has been to modify the genetic dosage of the natural prion protein in genetic models of different diseases. In this study, we take advantage of both approaches to examine whether this protein plays a role in the seeding and spreading of pathogenic tau. Our results point to a role of the natural prion protein in the emergence of pathogenic tau in a mouse model overexpressing the mutation P301S of the human tau gene. In contrast, its role is minor when sarkosyl-derived brain samples of Alzheimers disease are used. In fact, our results indicate that the use of this type of sample is not adequate to determine the role of a putative receptor in tau seeding and spreading.

neuroscience↗

bioRxiv2023

Development And Characterization Of A Non-Human Primate Model Of Disseminated Synucleinopathy

The presence of a widespread cortical synucleinopathy is the main neuropathological hallmark underlying clinical entities such as Parkinsons disease with dementia (PDD) and dementia with Lewy bodies (DLB). There currently is a pressing need for the development of non-human primate (NHPs) models of PDD and DLB to further overcome existing limitations in drug discovery. Here we took advantage of a retrogradely-spreading adeno-associated viral vector serotype 9 coding for the alpha-synuclein A53T mutated gene to induce a widespread synucleinopathy of cortical and subcortical territories innervating the putamen. Four weeks post-AAV deliveries animals were sacrificed and a comprehensive biodistribution study was conducted, comprising the quantification of neurons expressing alpha-synuclein, rostrocaudal distribution and their specific location. In brief, cortical afferent systems were found to be the main contributors to putaminal afferents (superior frontal and precentral gyrus in particular), together with neurons located in the caudal intralaminar nuclei and in the substantia nigra pars compacta (leading to thalamostriatal and nigrostriatal projections, respectively). Obtained data extends current models of synucleinopathies in NHPs, providing a reproducible platform enabling the adequate implementation of end-stage preclinical screening of new drugs targeting alpha-synuclein.

neuroscience↗

bioRxiv2023

Neuromelanin accumulation drives endogenous synucleinopathy in non-human primates

Although neuromelanin (NMel) is a dark pigment characteristic of dopaminergic neurons in the human substantia nigra pars compacta (SNpc), its potential role in the pathogenesis of Parkinsons disease (PD) has often been neglected since most commonly used laboratory animals lack NMel. Here we took advantage of adeno-associated viral vectors encoding the human tyrosinase gene for triggering a time-dependent NMel accumulation within SNpc dopaminergic neurons in macaques up to similar levels of pigmentation as observed in elderly humans. Furthermore, NMel accumulation induced an endogenous synucleinopathy mimicking intracellular inclusions typically observed in PD together with a progressive degeneration of NMel-expressing dopaminergic neurons. Moreover, Lewy body-like intracellular inclusions were observed in cortical areas of the frontal lobe receiving dopaminergic innervation, supporting a circuit-specific anterograde spread of endogenous synucleinopathy by permissive trans-synaptic templating. In summary, the conducted strategy resulted in the development and characterization of a new macaque model of PD matching the known neuropathology of this disorder with unprecedented accuracy. Most importantly, evidence is provided showing that intracellular aggregation of endogenous alpha-synuclein is triggered by NMel accumulation, therefore any therapeutic approach intended to decrease NMel levels may provide appealing choices for the successful implementation of novel PD therapeutics.

neuroscience↗