ORCID Profile
0000-0002-6702-4774
Current Organisation
Fundación ACE
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Publisher: Springer Science and Business Media LLC
Date: 26-03-2019
DOI: 10.1038/S41598-019-41443-3
Abstract: Soluble amyloid-β (Aβ) is considered to be a critical component in the pathogenesis of Alzheimer’s disease (AD). Evidence suggests that these non-fibrillar Aβ assemblies are implicated in synaptic dysfunction, neurodegeneration and cell death. However, characterization of these species comes mainly from studies in cellular or animal models, and there is little data in intact human s les due to the lack of adequate optical microscopic resolution to study these small structures. Here, to achieve super-resolution in all three dimensions, we applied Array Tomography (AT) and Stimulated Emission Depletion microscopy (STED), to characterize in postmortem human brain tissue non-fibrillar Aβ structures in amyloid plaques of cases with autosomal dominant and sporadic AD. Ultrathin sections scanned with super-resolution STED microscopy allowed the detection of small Aβ structures of the order of 100 nm. We reconstructed a whole human amyloid plaque and established that plaques are formed by a dense core of higher order Aβ species (~0.022 µm 3 ) and a peripheral halo of smaller Aβ structures (~0.003 µm 3 ). This work highlights the potential of AT-STED for human neuropathological studies.
Publisher: Elsevier BV
Date: 03-2019
Publisher: Oxford University Press (OUP)
Date: 23-11-2017
DOI: 10.1093/BRAIN/AWX275
Publisher: Springer Science and Business Media LLC
Date: 04-2022
DOI: 10.1038/S41588-022-01024-Z
Abstract: Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
Publisher: Wiley
Date: 07-12-2021
DOI: 10.1111/NAN.12781
Abstract: We report the neuropathological examination of a patient with Alzheimer's disease (AD) treated for 38 months with low doses of the BACE-1 inhibitor verubecestat. Brain examination showed small plaque size, reduced dystrophic neurites around plaques and reduced synaptic-associated Aβ compared with a group of age-matched untreated sporadic AD (SAD) cases. Our findings suggest that BACE-1 inhibition has an impact on synaptic soluble Aβ accumulation and neuritic derangement in AD.
Publisher: Research Square Platform LLC
Date: 23-03-2021
DOI: 10.21203/RS.3.RS-340117/V1
Abstract: Background. There is an urgent need for objective markers of Alzheimer’s disease (AD)-related cognitive impairment in people with Down syndrome (DS) to improve diagnosis, monitor disease progression and assess response to disease-modifying therapies. Previously, GluA4 and Neuronal Pentraxin 2 (NPTX2) showed limited potential as cerebrospinal fluid (CSF) markers of cognitive impairment in adults with DS. Here we compare the CSF profile of a panel of synaptic proteins (Calsyntenin-1, Neuroligin-2, Neurexin-2A, Neurexin-3A, Syntaxin-1B, Thy-1, VAMP-2) to that of NPTX2 and GluA4 in a large cohort of subjects with DS across the preclinical and clinical AD continuum and explore their correlation with cognitive impairment. Methods. We quantified the synaptic panel proteins by selected reaction monitoring in CSF from 20 non-trisomic cognitively normal controls (mean age 44) and 80 adults with DS grouped according to clinical AD diagnosis (asymptomatic, prodromal AD or AD dementia). We used regression analyses to determine CSF changes across the AD continuum and explored correlations with age, global cognitive performance (CAMCOG), episodic memory (modified cued-recall test mCRT) and CSF AD biomarkers, CSF Aβ 42:40 ratio, CSF Aβ 1-42 and CSF p-tau. P-values were adjusted for multiple testing. Results. In adults with DS, VAMP-2 was the only synaptic protein to correlate with episodic memory (delayed recall adj.p =.04) and age ( adj.p =.0008) and was the best correlate of CSF Aβ 42:40 ( adj.p =.0001) and CSF p-tau ( adj.p .0001). Compared to controls, mean VAMP-2 levels were lower in asymptomatic adults with DS only ( adj.p =.02). CSF levels of Neurexin-3A, Thy-1, Neurexin-2A, Calysntenin-1, Neuroligin-2, GluA4 and Syntaxin-1B all strongly correlated with NPTX2 ( p .0001), which was the only synaptic protein to show reduced CSF levels in DS at all AD stages compared to controls ( adj.p .002). Conclusion. CSF VAMP-2 represents a promising objective surrogate marker of cognitive failure in DS. VAMP-2 also has potential for use in AD clinical trials as a measure of synapse engagement and therapeutic response that does not directly measure the drug target (typically Aβ and tau).
Publisher: Springer Science and Business Media LLC
Date: 17-08-2020
DOI: 10.1186/S13024-020-00398-0
Abstract: Alzheimer’s disease (AD) is the major cause of death in adults with Down syndrome (DS). There is an urgent need for objective markers of AD in the DS population to improve early diagnosis and monitor disease progression. NPTX2 has recently emerged as a promising cerebrospinal fluid (CSF) biomarker of Alzheimer-related inhibitory circuit dysfunction in sporadic AD patients. The objective of this study was to evaluate NPTX2 in the CSF of adults with DS and to explore the relationship of NPTX2 to CSF levels of the PV interneuron receptor, GluA4, and existing AD biomarkers (CSF and neuroimaging). This is a cross-sectional, retrospective study of adults with DS with asymptomatic AD (aDS, n = 49), prodromal AD (pDS, n = 18) and AD dementia (dDS, n = 27). Non-trisomic controls ( n = 34) and patients with sporadic AD dementia (sAD, n = 40) were included for comparison. We compared group differences in CSF NPTX2 according to clinical diagnosis and degree of intellectual disability. We determined the relationship of CSF NPTX2 levels to age, cognitive performance (CAMCOG, free and cued selective reminding, semantic verbal fluency), CSF levels of a PV-interneuron marker (GluA4) and core AD biomarkers CSF Aβ 1–42 , CSF t-tau, cortical atrophy (magnetic resonance imaging) and glucose metabolism ([ 18 F]-fluorodeoxyglucose positron emission tomography). Compared to controls, mean CSF NPTX2 levels were lower in DS at all AD stages aDS (0.6-fold, adj. p 0.0001), pDS (0.5-fold, adj. p 0.0001) and dDS (0.3-fold, adj. p 0.0001). This reduction was similar to that observed in sporadic AD (0.5-fold, adj. p 0.0001). CSF NPTX2 levels were not associated with age ( p = 0.6), intellectual disability ( p = 0.7) or cognitive performance (all p 0.07). Low CSF NPTX2 levels were associated with low GluA4 in all clinical groups controls ( r 2 = 0.2, p = 0.003), adults with DS ( r 2 = 0.4, p 0.0001) and sporadic AD ( r 2 = 0.4, p 0.0001). In adults with DS, low CSF NPTX2 levels were associated with low CSF Aβ 1–42 ( r 2 0.3, p 0.006), low CSF t-tau ( r 2 0.3, p 0.001), increased cortical atrophy ( p 0.05) and reduced glucose metabolism ( p 0.05). Low levels of CSF NPTX2, a protein implicated in inhibitory circuit function, is common to sporadic and genetic forms of AD. CSF NPTX2 represents a promising CSF surrogate marker of early AD-related changes in adults with DS.
Publisher: Springer Science and Business Media LLC
Date: 28-06-2021
DOI: 10.1186/S13195-021-00861-0
Abstract: There is an urgent need for objective markers of Alzheimer’s disease (AD)-related cognitive impairment in people with Down syndrome (DS) to improve diagnosis, monitor disease progression, and assess response to disease-modifying therapies. Previously, GluA4 and neuronal pentraxin 2 (NPTX2) showed limited potential as cerebrospinal fluid (CSF) markers of cognitive impairment in adults with DS. Here, we compare the CSF profile of a panel of synaptic proteins (Calsyntenin-1, Neuroligin-2, Neurexin-2A, Neurexin-3A, Syntaxin-1B, Thy-1, VAMP-2) to that of NPTX2 and GluA4 in a large cohort of subjects with DS across the preclinical and clinical AD continuum and explore their correlation with cognitive impairment. We quantified the synaptic panel proteins by selected reaction monitoring in CSF from 20 non-trisomic cognitively normal controls (mean age 44) and 80 adults with DS grouped according to clinical AD diagnosis (asymptomatic, prodromal AD or AD dementia). We used regression analyses to determine CSF changes across the AD continuum and explored correlations with age, global cognitive performance (CAMCOG), episodic memory (modified cued-recall test mCRT) and CSF biomarkers, CSF Aβ 42:40 ratio, CSF Aβ 1-42 , CSF p-tau, and CSF NFL. P values were adjusted for multiple testing. In adults with DS, VAMP-2 was the only synaptic protein to correlate with episodic memory (delayed recall adj.p = .04) and age ( adj.p = .0008) and was the best correlate of CSF Aβ 42:40 ( adj.p = .0001), p-tau ( adj.p .0001), and NFL ( adj.p .0001). Compared to controls, mean VAMP-2 levels were lower in asymptomatic adults with DS only ( adj.p = .02). CSF levels of Neurexin-3A, Thy-1, Neurexin-2A, Calysntenin-1, Neuroligin-2, GluA4, and Syntaxin-1B all strongly correlated with NPTX2 ( p .0001), which was the only synaptic protein to show reduced CSF levels in DS at all AD stages compared to controls ( adj.p .002). These data show proof-of-concept for CSF VAMP-2 as a potential marker of synapse degeneration that correlates with CSF AD and axonal degeneration markers and cognitive performance.
Publisher: Wiley
Date: 02-2023
DOI: 10.1111/NAN.12879
Abstract: Amyloid precursor protein (APP) 𝛽‐C‐terminal fragment (𝛽CTF) may have a neurotoxic role in Alzheimer's disease (AD). 𝛽CTF accumulates in the brains of patients with sporadic (SAD) and genetic forms of AD. Synapses degenerate early during the pathogenesis of AD. We studied whether the 𝛽CTF accumulates in synapses in SAD, autosomal dominant AD (ADAD) and Down syndrome (DS). We used array tomography to determine APP at synapses in human AD tissue. We measured 𝛽CTF, A𝛽40, A𝛽42 and phosphorylated tau181 (p‐tau181) concentrations in brain homogenates and synaptosomes of frontal and temporal cortex of SAD, ADAD, DS and controls. APP colocalised with pre‐ and post‐synaptic markers in human AD brains. APP 𝛽CTF was enriched in AD synaptosomes. We demonstrate that 𝛽CTF accumulates in synapses in SAD, ADAD and DS. This finding might suggest a role for 𝛽CTF in synapse degeneration. Therapies aimed at mitigating 𝛽CTF accumulation could be potentially beneficial in AD.
Location: Spain
No related grants have been discovered for Raúl Núñez Llaves.