Diego Sepulveda-Falla

Diego Sepulveda-Falla
University Medical Center Hamburg - Eppendorf · Department of Neuropathology

Doctor of Medicine

About

94
Publications
15,717
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3,207
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Introduction
My work is focused in the molecular and neuropathological characterization of the Presenilin 1 E280A population suffering from early onset familial Alzheimer's Disease. Specific subjects of interest are non-amyloidogenic functions of Presenilin 1 and their phenotypic impact in the PS1 E280A population.
Additional affiliations
January 2018 - present
University Medical Center Hamburg - Eppendorf
Position
  • Group Leader
February 2015 - present
University Medical Center Hamburg - Eppendorf
Position
  • Junior Group leader
September 2012 - February 2015
University Medical Center Hamburg - Eppendorf
Position
  • PostDoc Position

Publications

Publications (94)
Article
Full-text available
Mild cognitive impairment (MCI) and pre-MCI have been proposed as stages preceding Alzheimer's disease (AD) dementia. We assessed descendants of individuals with a mutation in presenilin 1 (PSEN1) that causes familial AD, with the aim of identifying distinct stages of clinical progression to AD dementia. We retrospectively studied a cohort of desce...
Article
Full-text available
Presenilin 1 (PS1) mutations are the most common cause of early-onset familial Alzheimer's disease (EOFAD). They show a common phenotypic profile characterized by early age of onset, severe dementia and distinct neurodegeneration. The largest population of EOFAD carries the E280A mutation in PS1 and resides in Antioquia, Colombia, currently compris...
Article
Full-text available
Familial Alzheimer's disease (FAD) is characterized by autosomal dominant heritability and early disease onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD, with some of these patients presenting cerebellar damage with amyloid plaques and ataxia with unclear pathophysiology. A Colombian kindred c...
Article
Full-text available
Presenilin 1 (PS1) mutations are the most common cause of familial Alzheimer’s disease (FAD). PS1 also plays a role in cellular processes such as calcium homeostasis and autophagy. We hypothesized that mutant presenilins increase cellular vulnerability to stress. We stably expressed human PS1, mutant PS1E280A and mutant PS1Δ9 in mouse neuroblastoma...
Article
Full-text available
Presenilin-1 (PSEN1) mutations cause familial Alzheimer’s disease (FAD) characterized by early age of onset (AoO). Examination of a large kindred harboring the PSEN1-E280A mutation reveals a range of AoO spanning 30 years. The pathophysiological drivers and clinical impact of AoO variation in this population are unknown. We examined brains of 23 pa...
Article
Full-text available
Proteolytic cell surface release (‘shedding’) of the prion protein (PrP), a broadly expressed GPI-anchored glycoprotein, by the metalloprotease ADAM10 impacts on neurodegenerative and other diseases in animal and in vitro models. Recent studies employing the latter also suggest shed PrP (sPrP) to be a ligand in intercellular communication and criti...
Article
Background: Variants in APOE and PSEN1 (encoding apolipoprotein E and presenilin 1, respectively) alter the risk of Alzheimer's disease. We previously reported a delay of cognitive impairment in a person with autosomal dominant Alzheimer's disease caused by the PSEN1 E280A variant who also had two copies of the apolipoprotein E3 Christchurch varia...
Article
Full-text available
Two of every three persons living with dementia reside in low‐ and middle‐income countries (LMICs). The projected increase in global dementia rates is expected to affect LMICs disproportionately. However, the majority of global dementia care costs occur in high‐income countries (HICs), with dementia research predominantly focusing on HICs. This imb...
Article
Full-text available
A patient with the PSEN1 E280A mutation and homozygous for APOE3 Christchurch (APOE3Ch) displayed extreme resistance to Alzheimer’s disease (AD) cognitive decline and tauopathy, despite having a high amyloid burden. To further investigate the differences in biological processes attributed to APOE3Ch, we generated induced pluripotent stem (iPS) cell...
Article
Full-text available
INTRODUCTION Rate of cognitive decline (RCD) in Alzheimer's disease (AD) determines the degree of impairment for patients and of burden for caretakers. We studied the association of RCD with genetic variants in AD. METHODS RCD was evaluated in 62 familial AD (FAD) and 53 sporadic AD (SAD) cases, and analyzed by whole‐exome sequencing for associati...
Article
Background Vascular pathology is a main contributor to Alzheimer’s disease (AD) progression and severity. We have previously characterized vascular pathology in the PSEN1E280A Colombian kindred. In postmortem analyses we identified that the occipital cortex (OC) is the most affected region by small vessel disease (SVD), including other cortical are...
Article
Background We previously reported a case of a homozygous woman with the APOE3 Christchurch (R136S, APOE3Ch) variant who demonstrated extreme resistance to autosomal dominant Alzheimer’s disease (ADAD) caused by the PSEN1 E280A variant. In this study, we examined the potential protective effects of APOE3Ch against ADAD by characterizing the clinical...
Article
Background We have described two cases with ∼ 30 years of delayed disease onset among carriers of PSEN1 mutation E280A, suffering from familial Alzheimer’s disease (FAD). One case was homozygous for the ApoE Christchurch (hApoEch) mutation. This case showed sparse hyperphosphorylated tau (pTau) pathology in several cortical areas. The second case w...
Preprint
Proteolytic cell surface release (‘shedding’) of the prion protein (PrP), a broadly expressed GPI-anchored glycoprotein, by the metalloprotease ADAM10 impacts on neurodegenerative and other diseases in animal and in vitro models. Recent studies employing the latter also suggest shed PrP (sPrP) to be a ligand in intercellular communication and criti...
Article
Full-text available
INTRODUCTION We discovered that the APOE3 Christchurch (APOE3Ch) variant may provide resistance to Alzheimer's disease (AD). This resistance may be due to reduced pathological interactions between ApoE3Ch and heparan sulfate proteoglycans (HSPGs). METHODS We developed and characterized the binding, structure, and preclinical efficacy of novel anti...
Preprint
Full-text available
Autopsy studies have demonstrated that comorbid neurodegenerative and cerebrovascular disease occur in the great majority of subjects with Alzheimer disease dementia (ADD), and are likely to additively alter the rate of decline or severity of cognitive impairment. The most important of these are Lewy body disease (LBD), TDP-43 proteinopathy and cer...
Article
Full-text available
We characterized the world’s second case with ascertained extreme resilience to autosomal dominant Alzheimer’s disease (ADAD). Side-by-side comparisons of this male case and the previously reported female case with ADAD homozygote for the APOE3 Christchurch (APOECh) variant allowed us to discern common features. The male remained cognitively intact...
Article
Full-text available
Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by NOTCH3 mutations. Typical CADASIL is characterised by subcortical ischemic strokes due to severe arteriopathy and fibrotic thickening of small arteries. Arteriolar vascular smooth muscle cells (VSMCs) are the key target in CADASIL, but...
Article
Background: Depression is associated with Alzheimer's disease (AD). Objective: To evaluate the association between depressive symptoms and age of onset of cognitive decline in autosomal dominant AD, and to determine possible factors associated to early depressive symptoms in this population. Methods: We conducted a retrospective study to ident...
Preprint
Full-text available
Alzheimer′s disease (AD) is the most common cause of dementia among older adults. APOE3 Christchurch (R136S, APOE3Ch) variant homozygosity was reported in an individual with extreme resistance to autosomal dominant AD due to the PSEN1 E280A mutation. This subject had a delayed clinical age at onset and resistance to tauopathy and neurodegeneration...
Article
During the last 25 years we have collected 126 brains from the largest family in the world carrying PSEN1 mutation E280A and suffering from familial Alzheimer’s disease (FAD). Classical neuropathology scales rate all FAD cases as severe, overlooking the degree of heterogeneity observed in these cases. Here we present a new approach involving High T...
Article
Full-text available
In response to brain insults, astrocytes become reactive, promoting protection and tissue repair. However, astroglial reactivity is typical of brain pathologies, including Alzheimer's disease (AD). Considering the heterogeneity of the reac-tive response, the role of astrocytes in the course of different forms of AD has been underestimated. Colombia...
Article
Full-text available
Prion diseases are neurodegenerative diseases that affect humans and animals. They are always fatal and, to date, no treatment exists. The hallmark of prion disease pathophysiology is the misfolding of an endogenous protein, the cellular prion protein (PrPC), into its disease-associated isoform PrPSc. Besides the aggregation and deposition of misfo...
Article
Full-text available
We describe in vivo follow-up PET imaging and postmortem findings from an autosomal dominant Alzheimer’s disease (ADAD) PSEN1 E280A carrier who was also homozygous for the APOE3 Christchurch (APOE3ch) variant and was protected against Alzheimer’s symptoms for almost three decades beyond the expected age of onset. We identified a distinct anatomical...
Article
Full-text available
We studied small vessel disease (SVD) pathology in Familial Alzheimer's disease (FAD) subjects carrying the presenilin 1 (PSEN1) p.Glu280Ala mutation in comparison to those with sporadic Alzheimer's disease (SAD) as a positive control for Alzheimer's pathology and Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalo...
Article
Full-text available
Pathological hallmarks of Alzheimer's disease (AD) include deposition and accumulation of amyloid-β (Aβ), neurofibrillary tangle formation, and neuronal loss. Pathogenesis of presymptomatic disease stages remains elusive, although studies suggest that the early structural and functional alterations likely occur at neuronal dendritic spines. Presymp...
Article
Full-text available
Neurological complications are common in COVID-19. Although SARS-CoV-2 has been detected in patients’ brain tissues, its entry routes and resulting consequences are not well understood. Here, we show a pronounced upregulation of interferon signaling pathways of the neurovascular unit in fatal COVID-19. By investigating the susceptibility of human i...
Article
Full-text available
Alzheimer’s disease is the most common cause of dementia. Biological definitions of AD are limited to the cerebral burden of amyloid β plaques, neurofibrillary pathology and neurodegeneration. However, current evidence suggests various features of small vessel disease (SVD) are part and parcel of and covertly modify both sporadic and familial AD. N...
Article
Full-text available
Alzheimer's disease pathology is characterized by β-amyloid plaques and neurofibrillary tangles. Amyloid precursor protein is processed by β and γ secretase, resulting in the production of β-amyloid peptides with a length ranging from 38 to 43 amino acids. Presenilin 1 (PS1) is the catalytic unit of γ-secretase, and more than 200 PS1 pathogenic mut...
Article
Background Cerebrospinal fluid (CSF) p‐tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer’s disease (AD) reflecting abnormal tau metabolism in the brain. We have recently shown that also plasma p‐tau181 is a promising biomarker for AD (Janelidze et al, Nature Medicine , 2020). We now evaluate whether CSF p‐tau217...
Article
Full-text available
Alzheimer’s type dementia (AD) exhibits clinical heterogeneity, as well as differences in disease progression, as a subset of patients with a clinical diagnosis of AD progresses more rapidly (rpAD) than the typical AD of slow progression (spAD). Previous findings indicate that low cerebrospinal fluid (CSF) content of cell-free mitochondrial DNA (cf...
Article
Full-text available
Familial Alzheimer’s Disease (FAD) caused by Presenilin-1 (PS1) mutations is characterized by early onset, cognitive impairment, and dementia. Impaired gamma secretase function favors production of longer beta-amyloid species in PS1 FAD. The PS1 E280A mutation is the largest FAD kindred under study. Here, we studied beta-amyloid deposits in PS1 E28...
Article
Importance There are limitations in current diagnostic testing approaches for Alzheimer disease (AD). Objective To examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnostic biomarker for AD. Design, Setting, and Participants Three cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 particip...
Article
Background: Neurofilament light chain (NfL) is a promising biomarker of active axonal injury and neuronal degeneration. We aimed to characterise cross-sectional and longitudinal plasma NfL measurements and determine the age at which NfL concentrations begin to differentiate between carriers of the presenilin 1 (PSEN1) E280A (Glu280Ala) mutation an...
Article
Sporadic Alzheimer's disease (SAD) is the most common form of dementia, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most frequent hereditary ischemic small vessel disease of the brain. Relevant biomarkers or specific metabolic signatures could provide powerful tools to manage these...
Chapter
Oxidative stress is well recognized as an important pathological component in many conditions that involve neuronal degeneration and dementia. In this chapter, we summarize experimental data from the literature on the role of oxidative stress in common forms of dementia including Alzheimer's and Parkinson's diseases and vascular and frontotemporal...
Article
Full-text available
Neuroserpin is a serine protease inhibitor of the nervous system required for normal synaptic plasticity and regulating cognitive, emotional and social behavior in mice. The high expression level of neuroserpin detected at late stages of nervous system formation in most regions of the brain points to a function in neurodevelopment. In order to eval...
Article
Full-text available
Astrogliosis and activation of microglia are hallmarks of prion diseases in humans and animals. Both were viewed to be rather independent events in disease pathophysiology, with proinflammatory microglia considered to be the potential neurotoxic species at late disease stages. Recent investigations have provided substantial evidence that a proinfla...
Article
Full-text available
Alzheimer’s disease (AD) is characterized by intracellular tau aggregates and extracellular deposition of amyloid-β (Aβ). The major genetic risk factor to develop AD is the Apolipoprotein E isoform 4 (ApoE4). ApoE4 may directly affect Aβ pathology, yet the exact role of ApoE4 in the progression of AD remains unclear. Although astrocytes are the mai...
Data
Proinflammatory signaling is altered in N9.ApoE4 after LPS treatment. The NanoString nCounter Mouse Neuroinflammation Panel was used to evaluate gene expression analysis of inflammation-relevant genes, in N9.ApoE3 and N9.ApoE4 after 24 h of treatment with 100 ng/ml LPS. (A) Heatmap depicting cluster analysis for gene expression levels of 389 out of...
Data
Two-way ANOVA analysis of gene expression levels between untreated N9.ApoE3, LPS treated N9.ApoE3, and LPS treated N9.ApoE4 cells.
Data
ROCK1 expression is dysregulated in N9.ApoE4. (A) Western Blot analysis of ROCK1. PDI displays protein loading. (B) Quantification shows a significant downregulation of ROCK1 in N9.ApoE4 in comparison to N9.Wt (n = 9). (C) Quantification of RNA-expression level of Rock1 shows a significant decrease in N9.ApoE4 in comparison to N9.Wt (n = 7). Murine...
Data
Pairwise analysis of gene expression levels between LPS treated N9.ApoE3, and N9.ApoE4 cells.
Data
Actin expression is increased in N9.ApoE4 cells. (A) qPCR analysis of murine ApoE RNA-expression in transfected cells normalized against murine GapDH levels. All cell lines except N9.ApoEKO express murine ApoE at a very low, endogenous level. (B) Actin expression of N9.ApoE4 was significant increase in microglia cells when investigated using confoc...
Data
Pairwise analysis of gene expression levels between untreated N9.ApoE3, and LPS treated N9.ApoE3 cells.
Article
Activated microglia represent a common pathological feature of neurodegenerative diseases. Sporadic Creutzfeldt–Jakob disease (sCJD) patients show more pronounced microglial activation than Alzheimer's disease (AD) patients. Whether these differences are due to differences in disease kinetics or represent disease‐specific changes is unknown. We inv...
Article
Significance The clinical and pathological variability among patients with Alzheimer’s disease (AD) remains largely unexplained. Evidence is growing that this heterogeneity may be influenced by the heterogeneous molecular architecture of misfolded amyloid-β peptide (Aβ) in the brain. To test this hypothesis, we used unique fluorescent ligands to in...
Article
The identification of mutations modifying the age of onset (AOO) in Alzheimer's disease (AD) is crucial for understanding the natural history of AD and, therefore, for early interventions. Patients with sporadic AD (sAD) from a genetic isolate in the extremes of the AOO distribution were whole-exome genotyped. Single-and multi-locus linear mixed-ef...
Article
Full-text available
The mechanisms leading to amyloid-β (Aβ) accumulation in sporadic Alzheimer disease (AD) are unknown but both increased production or impaired clearance likely contribute to aggregation. To understand the potential roles of the extracellular matrix proteoglycan Testican-1 in the pathophysiology of AD, we used samples from AD patients and controls a...
Article
This commentary highlights the study by Frau-Mendez and coworkers in this issue of Brain Pathology (xxx) in which the authors show evidence for involvement of mitochondria in the pathophysiology of fatal familial insomnia (FFI). Using genetic, biochemical and morphological means, they provide a comprehensive picture of the degree of mitochondrial d...
Article
Full-text available
Purpose: The aim of this study was to investigate the epidermal growth factor receptor (EGFR) status in ependymoma specimens, as there is a need for new prognostic and druggable targets in this disease. Methods: Ependymomas (WHO grade II, n = 40; WHO grade III, n = 15) located spinal (n = 35), infratentorial (n = 14), and supratentorial (n = 6)...
Article
Full-text available
Alzheimer’s disease (AD) age of onset (ADAOO) varies greatly between individuals, with unique causal mutations suggesting the role of modifying genetic and environmental interactions. We analyzed ~50 000 common and rare functional genomic variants from 71 individuals of the ‘Paisa’ pedigree, the world’s largest pedigree segregating a severe form of...
Article
Presenilin (PSEN) pathogenic mutations cause familial Alzheimer's disease (AD [FAD]) in an autosomal-dominant manner. The extent to which the healthy and diseased alleles influence each other to cause neurodegeneration remains unclear. In this study, we assessed γ-secretase activity in brain samples from 15 nondemented subjects, 22 FAD patients har...
Article
Full-text available
Presenilin (PSEN) pathogenic mutations cause familial Alzheimer's disease (AD [FAD]) in an autosomal-dominant manner. The extent to which the healthy and diseased alleles influence each other to cause neurodegeneration remains unclear. In this study, we assessed gamma-secretase activity in brain samples from 15 nondemented subjects, 22 FAD patients...
Conference Paper
Full-text available
-INTRODUCTION. (1) Recent evidence shows that familial Alzheimer´s disease (AD)-associated presenilin-1 mutations alters calcium homeostasis in cellular models (http://www.ncbi.nlm.nih.gov/pubmed/22842534) and in fAD patients (Sepulveda-Falla, 2014), leading to neurodegeneration. (2) Previous computer simulations have suggested that in AD there are...
Article
Full-text available
Background: In this descriptive study of a case series a comparison was made of neuropathological, neuropsychological and imaging characteristics from two groups of patients with Alzheimer's Disease (AD). One group with sporadic AD (SAD) and another group with familial AD (FAD). Methods: For that, 460 deparaffinized slides from brain tissue were o...
Article
Full-text available
Familial Alzheimer's disease (FAD) is characterized by autosomal dominant heritability and early disease onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD, with some of these patients presenting cerebellar damage with amyloid plaques and ataxia with unclear pathophysiology. A Colombian kindred c...
Article
Full-text available
Alzheimer's disease is the most common form of dementia and the generation of oligomeric species of amyloid-β is causal to the initiation and progression of it. Amyloid-β oligomers bind to the N-terminus of plasma membrane-bound cellular prion protein (PrP(C)) initiating a series of events leading to synaptic degeneration. Composition of bound amyl...