{"id":37,"date":"2022-05-25T18:08:14","date_gmt":"2022-05-25T16:08:14","guid":{"rendered":"http:\/\/molneup-ad.org\/?page_id=37"},"modified":"2025-06-24T11:26:33","modified_gmt":"2025-06-24T09:26:33","slug":"projects","status":"publish","type":"page","link":"https:\/\/molneup-ad.org\/index.php\/projects\/","title":{"rendered":"Projects"},"content":{"rendered":"\n<p>Deciphering the molecular mechanisms of pathology and disease variability of sporadic and familiar Alzheimer\u2019s.<\/p>\n\n\n\n<p>For the last 10 years we have characterized the neuropathology of the brains collected from the largest population in the world sharing a single common mutation (E280A) in PSEN1. We have learned that there is wide variability in the pathological presentation of Alzheimer\u2019s in these brains, often associated with modifications in its clinical presentation. Furthermore, we have identified specific cellular and molecular features for this mutation following and translational approach, from pathological features identified in the brains to cellular and animal models. We expect that all the knowledge obtained from these cases will help to a better understanding of both familial and sporadic Alzheimer\u2019s presentations in view of the development of successful therapies for the disease.<\/p>\n\n\n\n<hr class=\"wp-block-separator has-css-opacity is-style-wide\"\/>\n\n\n\n<p class=\"has-medium-font-size\"><strong>In-depth phenotypic characterization of familial and sporadic Alzheimer&#8217;s neuropathology<\/strong><\/p>\n\n\n\n<p class=\"has-text-align-center\"><img loading=\"lazy\" decoding=\"async\" width=\"400\" height=\"387\" class=\"wp-image-40\" style=\"width: 400px;\" src=\"https:\/\/molneup-ad.org\/wp-content\/uploads\/2022\/05\/Picture1.png\" alt=\"Characterization of amyloid plaques\" srcset=\"https:\/\/molneup-ad.org\/wp-content\/uploads\/2022\/05\/Picture1.png 606w, https:\/\/molneup-ad.org\/wp-content\/uploads\/2022\/05\/Picture1-300x291.png 300w\" sizes=\"auto, (max-width: 400px) 85vw, 400px\" \/><\/p>\n\n\n\n<p>Our colleagues in Colombia have collected close to 300 Alzheimer&#8217;s disease brains so far. 130 brains donated by PSEN1 E280A carriers and more than 150 from sporadic Alzheimer&#8217;s patients. Using classic neuropathological methods, we are studying and diagnosing all those brains to assess variability in the distribution and pattern of presentation of Amyloid beta (A\u03b2) plaques and hyperphosphorylated tangles deposition. We are now using high throughput methods, molecular and neuropathological, to assess phenotypic variability and its possible relation with clinical presentation subtypes together with colleagues in Colombia, Brazil and United States. <\/p>\n\n\n\n<p><strong>Collaborators:<\/strong><\/p>\n\n\n\n<p><a href=\"https:\/\/www.uke.de\/allgemein\/arztprofile-und-wissenschaftlerprofile\/arztprofilseite_markus_glatzel.html\" data-type=\"URL\" data-id=\"https:\/\/www.uke.de\/allgemein\/arztprofile-und-wissenschaftlerprofile\/arztprofilseite_markus_glatzel.html\">Prof. Markus Glatzel<\/a><\/p>\n\n\n\n<p>Prof. Francisco Lopera <\/p>\n\n\n\n<p><a href=\"https:\/\/gna.org.co\/neurociencia-clinica\/\" data-type=\"link\" data-id=\"https:\/\/gna.org.co\/neurociencia-clinica\/\">Dr. David Aguill\u00f3n<\/a><\/p>\n\n\n\n<p><a href=\"https:\/\/bv.fapesp.br\/pt\/pesquisador\/661492\/claudia-kimie-suemoto\/\">Prof. Claudia Suemoto<\/a><\/p>\n\n\n\n<p><strong>Funding: <\/strong><\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>DFG &#8211; <em>Identifizierung von Hirnzelltyps-pezifischen Genregulationsnetzwerken bei Patienten mit famili\u00e4rer Alzheimer-Krankheit PSEN1 E280A.<\/em> <em><a href=\"https:\/\/gepris.dfg.de\/gepris\/projekt\/458854216\" data-type=\"URL\" data-id=\"https:\/\/gepris.dfg.de\/gepris\/projekt\/458854216\">458854216<\/a><\/em><\/li>\n<\/ul>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Alzheimer&#8217;s Association &#8211; AI assisted neuropathological assessment of sporadic Alzheimer&#8217;s cases 23AARGD-1030514<\/li>\n<\/ul>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Digital Neuropathology &#8211; Project GADIR<\/li>\n<\/ul>\n\n\n\n<hr class=\"wp-block-separator has-css-opacity is-style-wide\"\/>\n\n\n\n<p class=\"has-medium-font-size\"><strong>Identification of mechanisms of resistance and disease modifiers in familial Alzheimer\u2019s disease<\/strong><\/p>\n\n\n<div class=\"wp-block-image\">\n<figure class=\"aligncenter size-full is-resized\"><img loading=\"lazy\" decoding=\"async\" width=\"560\" height=\"509\" src=\"https:\/\/molneup-ad.org\/wp-content\/uploads\/2022\/05\/Picture2-1.png\" alt=\"Mechanisms of resistance to AD\" class=\"wp-image-42\" style=\"width:447px;height:406px\" srcset=\"https:\/\/molneup-ad.org\/wp-content\/uploads\/2022\/05\/Picture2-1.png 560w, https:\/\/molneup-ad.org\/wp-content\/uploads\/2022\/05\/Picture2-1-300x273.png 300w\" sizes=\"auto, (max-width: 560px) 85vw, 560px\" \/><\/figure>\n<\/div>\n\n\n<p>In some PSEN1 E280A cases we have detected a correlation between decreased cortical Tau pathology and delayed dementia onset, sometimes more than 30 years. These special cases have provided clues for molecular mechanisms of resistance against the pathophysiology of the disease. However, there are even more rare cases that although presenting with full-fledged Alzheimer\u2019s pathology, also present with the same degree of delayed disease onset. These cases offer a clue about mechanisms of resilience against Alzheimer\u2019s disease and neurodegeneration in general. A deep understanding of mechanisms of resistance and resilience against Alzheimer\u2019s disease is a necessary step for the development of successful therapies. Furthermore, age at disease onset is not the only phenotypic feature indicating risk or protection. We are also exploring genetic modifiers of cognitive decline.<\/p>\n\n\n\n<p><strong>Collaborators:<\/strong><\/p>\n\n\n\n<p>Prof. Francisco Lopera<\/p>\n\n\n\n<p><a href=\"https:\/\/www.uke.de\/english\/physicians-and-scientists\/wissenschaftlerprofilseite_susanne_krasemann.html\" data-type=\"URL\" data-id=\"https:\/\/www.uke.de\/english\/physicians-and-scientists\/wissenschaftlerprofilseite_susanne_krasemann.html\">Dr. Susanne Krasemann<\/a><\/p>\n\n\n\n<p><a href=\"https:\/\/eye.hms.harvard.edu\/josepharboleda\" data-type=\"URL\" data-id=\"https:\/\/eye.hms.harvard.edu\/josepharboleda\">Dr. Joseph F. Arboleda-Vel\u00e1squez<\/a><\/p>\n\n\n\n<p><a href=\"https:\/\/mapp.mgh.harvard.edu\/yakeel-quiroz\/\">Dr. Yakeel T. Quiroz<\/a><\/p>\n\n\n\n<p><strong>Funding:<\/strong> <\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Good Ventures &#8211; <em><a href=\"https:\/\/www.goodventures.org\/our-portfolio\/grants\/uke-hamburg-eppendorf-alzheimers-disease-research-diego-sepulveda-falla\" target=\"_blank\" rel=\"noreferrer noopener\">Mechanisms associated with resilience to Alzheimer&#8217;s disease<\/a>.<\/em><\/li>\n<\/ul>\n\n\n\n<ul class=\"wp-block-list\">\n<li>B\u00fcrgerstiftung Hannover \/ Wilhelm-Emanuel-Zach-Stiftung &#8211; Identifizierung und Validierung von protektiven Mechanismen in Gehirnen von Patienten, welche vor der Alzheimer-Krankheit gesch\u00fctzt sind. Projekt 2023-119.<\/li>\n<\/ul>\n\n\n\n<ul class=\"wp-block-list\">\n<li>B\u00fcrgerstiftung Hannover \/ Wilhelm-Emanuel-Zach-Stiftung &#8211; Identifizierung und Validierung von protektiven Mechanismen in Gehirnen von Patienten, welche vor der Alzheimer-Krankheit gesch\u00fctzt sind. Projekt 2025-89.<\/li>\n<\/ul>\n\n\n\n<hr class=\"wp-block-separator has-css-opacity is-style-wide\"\/>\n\n\n\n<p class=\"has-medium-font-size\"><strong>Small vascular pathology in familial Alzheimer\u2019s disease<\/strong> <\/p>\n\n\n<div class=\"wp-block-image\">\n<figure class=\"aligncenter size-full is-resized\"><img loading=\"lazy\" decoding=\"async\" width=\"617\" height=\"475\" src=\"https:\/\/molneup-ad.org\/wp-content\/uploads\/2022\/05\/Picture3.png\" alt=\"Isolated microvessels immunofluorescence\" class=\"wp-image-43\" style=\"width:576px;height:443px\" srcset=\"https:\/\/molneup-ad.org\/wp-content\/uploads\/2022\/05\/Picture3.png 617w, https:\/\/molneup-ad.org\/wp-content\/uploads\/2022\/05\/Picture3-300x231.png 300w\" sizes=\"auto, (max-width: 617px) 85vw, 617px\" \/><figcaption class=\"wp-element-caption\">Credits: Lisa Littau<\/figcaption><\/figure>\n<\/div>\n\n\n<p>A high number of sporadic Alzheimer\u2019s disease cases present with vascular pathology together with the more common Alzheimer\u2019s neuropathological hallmarks. For long these vascular changes have been attributed to Ab accumulation in blood vessels. We have identified that in familial Alzheimer\u2019s cases there are other vascular changes not directly associated with Ab accumulation, and that could be related with specific cellular functions of Presenilin-1. We are currently identifying the molecular pathways associated to small vessel pathology in PSEN1 mutants and their possible impact in clinical phenotypes.<\/p>\n\n\n\n<p><strong>Collaborators:<\/strong><\/p>\n\n\n\n<p>Prof. Francisco Lopera<\/p>\n\n\n\n<p>Dr. Joseph F. Arboleda-Velasquez<\/p>\n\n\n\n<p>Dr. Yakeel T. Quiroz<\/p>\n\n\n\n<p><a href=\"https:\/\/www.ncl.ac.uk\/medical-sciences\/people\/profile\/rajkalaria.html\" data-type=\"URL\" data-id=\"https:\/\/www.ncl.ac.uk\/medical-sciences\/people\/profile\/rajkalaria.html\">Prof. Raj Kalaria<\/a><\/p>\n\n\n\n<p><strong>Funding:<\/strong> <\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>NIH &#8211; <em>Charting vascular contributions to white matter disease in familial Alzheimer&#8217;s disease and CADASIL. <a href=\"https:\/\/grantome.com\/grant\/NIH\/RF1-NS110048-01S1\" data-type=\"URL\" data-id=\"https:\/\/grantome.com\/grant\/NIH\/RF1-NS110048-01S1\">RF1NS110048-01S1<\/a><\/em><\/li>\n<\/ul>\n\n\n\n<hr class=\"wp-block-separator has-css-opacity is-style-wide\"\/>\n\n\n\n<p class=\"has-medium-font-size\"><strong>Mechanisms of stress and cellular vulnerability in PSEN1 mutants<\/strong><\/p>\n\n\n<div class=\"wp-block-image\">\n<figure class=\"aligncenter size-full is-resized\"><img loading=\"lazy\" decoding=\"async\" width=\"594\" height=\"594\" src=\"https:\/\/molneup-ad.org\/wp-content\/uploads\/2022\/05\/Picture4.png\" alt=\"Astrocytes 3D culture in matrigel\" class=\"wp-image-44\" style=\"width:508px;height:508px\" srcset=\"https:\/\/molneup-ad.org\/wp-content\/uploads\/2022\/05\/Picture4.png 594w, https:\/\/molneup-ad.org\/wp-content\/uploads\/2022\/05\/Picture4-300x300.png 300w, https:\/\/molneup-ad.org\/wp-content\/uploads\/2022\/05\/Picture4-150x150.png 150w\" sizes=\"auto, (max-width: 594px) 85vw, 594px\" \/><figcaption class=\"wp-element-caption\">Credit: Pinzhang Lu<\/figcaption><\/figure>\n<\/div>\n\n\n<p>From the findings identified in patient\u2019s brain tissue we have learned that PSEN1 mutant cells are more vulnerable to cellular stress via mechanisms independent of A<bdo lang=\"gr\" dir=\"ltr\">\u03b2<\/bdo> accumulation or A\u03b2 altered production. Instead, gamma secretase disfunction has an impact in cellular homeostasis rendering cells more vulnerable to stress. We have confirmed these findings in various cellular models, and we are currently assessing the degree of vulnerability in specific cellular populations in the brain and their possible impact in neurodegeneration. These findings can be relevant for unraveling Alzheimer\u2019s the early onset and high severity typically found in familial Alzheimer\u2019s disease patients. For this project we are leveraging on single nuclei and spatial transcriptomics to identify vulnerable cell types.<\/p>\n\n\n\n<p><strong>Funding: <\/strong><\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>DFG &#8211; <em>Identifizierung von Hirnzelltyps-pezifischen Genregulationsnetzwerken bei Patienten mit famili\u00e4rer Alzheimer-Krankheit PSEN1 E280A.<\/em> <em>458854216<\/em><\/li>\n<\/ul>\n\n\n\n<p><\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>B\u00fcrgerstiftung Hannover \/ Wilhelm-Emanuel-Zach-Stiftung &#8211; Identifizierung und Validierung von protektiven Mechanismen in Gehirnen von Patienten, welche vor der Alzheimer-Krankheit gesch\u00fctzt sind. Projekt 2023-119.<\/li>\n<\/ul>\n\n\n\n<p><\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>B\u00fcrgerstiftung Hannover \/ Wilhelm-Emanuel-Zach-Stiftung &#8211; Identifizierung und Validierung von protektiven Mechanismen in Gehirnen von Patienten, welche vor der Alzheimer-Krankheit gesch\u00fctzt sind. Projekt 2025-89.<\/li>\n<\/ul>\n\n\n\n<hr class=\"wp-block-separator has-css-opacity is-style-wide\"\/>\n","protected":false},"excerpt":{"rendered":"<p>Deciphering the molecular mechanisms of pathology and disease variability of sporadic and familiar Alzheimer\u2019s. For the last 10 years we have characterized the neuropathology of the brains collected from the largest population in the world sharing a single common mutation (E280A) in PSEN1. We have learned that there is wide variability in the pathological presentation &hellip; <a href=\"https:\/\/molneup-ad.org\/index.php\/projects\/\" class=\"more-link\">Continue reading<span class=\"screen-reader-text\"> &#8220;Projects&#8221;<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"parent":0,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"footnotes":""},"class_list":["post-37","page","type-page","status-publish","hentry"],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v26.6 - https:\/\/yoast.com\/wordpress\/plugins\/seo\/ -->\n<title>Projects - Molecular Neuropathology of Alzheimer&#039;s Disease - MoNeA<\/title>\n<meta name=\"description\" content=\"Translational research and molecular neuropathology of Alzheimer&#039;s disease. Dr. Diego Seoulveda-Falla&#039;s Lab\" \/>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/molneup-ad.org\/index.php\/projects\/\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Projects - Molecular Neuropathology of Alzheimer&#039;s Disease - MoNeA\" \/>\n<meta property=\"og:description\" content=\"Translational research and molecular neuropathology of Alzheimer&#039;s disease. Dr. Diego Seoulveda-Falla&#039;s Lab\" \/>\n<meta property=\"og:url\" content=\"https:\/\/molneup-ad.org\/index.php\/projects\/\" \/>\n<meta property=\"og:site_name\" content=\"Molecular Neuropathology of Alzheimer&#039;s Disease - MoNeA\" \/>\n<meta property=\"article:modified_time\" content=\"2025-06-24T09:26:33+00:00\" \/>\n<meta property=\"og:image\" content=\"http:\/\/molneup-ad.org\/wp-content\/uploads\/2022\/05\/Picture1.png\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:site\" content=\"@diegosflab\" \/>\n<meta name=\"twitter:label1\" content=\"Estimated reading time\" \/>\n\t<meta name=\"twitter:data1\" content=\"4 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\/\/schema.org\",\"@graph\":[{\"@type\":\"WebPage\",\"@id\":\"https:\/\/molneup-ad.org\/index.php\/projects\/\",\"url\":\"https:\/\/molneup-ad.org\/index.php\/projects\/\",\"name\":\"Projects - Molecular Neuropathology of Alzheimer&#039;s Disease - MoNeA\",\"isPartOf\":{\"@id\":\"https:\/\/molneup-ad.org\/#website\"},\"primaryImageOfPage\":{\"@id\":\"https:\/\/molneup-ad.org\/index.php\/projects\/#primaryimage\"},\"image\":{\"@id\":\"https:\/\/molneup-ad.org\/index.php\/projects\/#primaryimage\"},\"thumbnailUrl\":\"http:\/\/molneup-ad.org\/wp-content\/uploads\/2022\/05\/Picture1.png\",\"datePublished\":\"2022-05-25T16:08:14+00:00\",\"dateModified\":\"2025-06-24T09:26:33+00:00\",\"description\":\"Translational research and molecular neuropathology of Alzheimer's disease. 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