{"id":817,"date":"2025-06-23T17:26:10","date_gmt":"2025-06-23T17:26:10","guid":{"rendered":"http:\/\/changingfaceofamerica.com\/?p=817"},"modified":"2025-06-23T17:26:10","modified_gmt":"2025-06-23T17:26:10","slug":"neuropathologically-late-is-defined-and-staged-by-virtue-of-the-presence-of-intracytoplasmic-deposits-of-tdp-43-within-specific-reproducible-areas-of-the-neuraxis-early-stages-originate-in","status":"publish","type":"post","link":"http:\/\/changingfaceofamerica.com\/?p=817","title":{"rendered":"\ufeffNeuropathologically, LATE is defined and staged by virtue of the presence of intracytoplasmic deposits of TDP-43 within specific, reproducible areas of the neuraxis; early stages originate inclusions within medial limbic structures, while advanced stages show inclusions in cerebral neocortex"},"content":{"rendered":"

\ufeffNeuropathologically, LATE is defined and staged by virtue of the presence of intracytoplasmic deposits of TDP-43 within specific, reproducible areas of the neuraxis; early stages originate inclusions within medial limbic structures, while advanced stages show inclusions in cerebral neocortex. paraffin-embedded tissues, 2G11 and 2H1 robustly identified the classic inclusions of ALS and FTLD-TDP, and efficaciously provided a diagnosis of LATE in cases of AD and LBD. These novel antibodies label aberrant intracytoplasmic protein inclusions without relying on hyperphosphorylated epitopes, and provide elegant discrimination between TDP-43 and tau neurofibrillary tangles within neurodegenerative comorbidity. Keywords:TDP-43, LATE, FTLD-TDP, ALS, immunohistochemistry, neuropathology == Introduction == The importance of transactive response DNA-binding protein of 43 kilodaltons (TDP-43) in neurodegenerative diseases became clear upon the discovery that aberrant, cytoplasmic inclusions of the protein comprise the pathologic substrate of most cases of sporadic amyotrophic lateral sclerosis (ALS) [1]. Similarly, the protein deposits of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), whose inclusions were previously characterized only by their non-specific association to ubiquitin, were found to be composed of aberrant cytoplasmic TDP-43, ultimately warranting a taxonomic change to frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP) [1]. TDP-43 was initially discovered as a protein capable of binding the transactive response DNA element of the human immunodeficiency computer virus (HIV) [2]. In its physiologic state, the TDP-43 protein primarily localizes to the cell nucleus, reflective of its function related to regulation of RNA transcription, splicing, and translation via RNA and DNA interactions through its RNA recognition motif 1 (RRM1) and RNA recognition motif 2 (RRM2) domains [3,4]. In mouse models, TDP-43 has been shown to be expressed throughout the primitive neuroepithelium during embryonic development, and within cerebral neocortical, hippocampal, cerebellar, and spinal cord structures in adult tissue [5]. TDP-43 exhibits a high degree of conservation between species [6], with approximately 96% of amino acid residue concordance with mouse (Mus musculus) TAK-779<\/a> protein (https:\/\/www.ncbi.nlm.nih.gov\/protein\/Q13148.1andhttps:\/\/www.ncbi.nlm.nih.gov\/protein\/NP_663531.1) [6]. As the study of TDP-43s contribution to neurodegeneration continued, it became increasingly acknowledged TAK-779 that TDP-43 inclusions occur outside of the classical distribution associated with ALS and FTLD-TDP. TDP-43 proteinopathy outside of the ALS and FTLD spectrum has been ascribed to evolving terminologies, which have included hippocampal sclerosis of aging and cerebral age-related TDP-43 and sclerosis (CARTS) [7,8]. In a recent attempt to discretely articulate TDP-43 proteinopathy outside of ALS and FTLD, the term Limbic-Predominant Age-Related TDP-43 encephalopathy (LATE) was proposed [9]. LATE explains an amnestic dementia syndrome arising in elderly populations that may occur in isolation or (more commonly) co-morbidly with other neurodegenerative diseases. Neuropathologically, LATE is usually defined and staged by virtue of the presence of intracytoplasmic deposits of TDP-43 within specific, reproducible areas of the neuraxis; early stages originate inclusions within medial limbic structures, while advanced stages show inclusions in cerebral neocortex. Although previous iterations of FGF10<\/a> staging schemes for non-ALS\/FTLD TDP-43 proteinopathy provided for up to five stages of disease stratification [10,11], the current working group criteria integrate the staging of LATE neuropathologic change (LATE-NC) into stage 1, 2, and 3 TAK-779 disease based upon progressive involvement of amygdala, hippocampus, and midfrontal neocortex, respectively [9]. ALS, FTLD-TDP, and LATE have each been described as capable of producing a neurodegenerative condition independently. However, it is increasingly acknowledged that TDP-43 proteinopathies frequently occur in the context of comorbidity with other neurodegenerative diseases [12], especially LATE [13,14]. As such, sensitive and specific tools for detecting aberrant deposits of TDP-43 protein are needed in order to effectively detect and stage disease, as well as clarify associations between proteinopathies. The neuropathological evaluation of these diseases occurs in human post-mortem material and is most commonly predicated upon study of formalin-fixed, paraffin embedded (FFPE) tissue. Within this tissue medium, immunohistochemistry represents a versatile and widely available testing modality. In this study, we describe the generation and characterization of two novel mouse-derived monoclonal antibodies with elegant specificity for aberrant human TDP-43 inclusions within FFPE tissue of TDP-43 proteinopathies. == Materials and Methods == == Mice == All animal experimental procedures were performed according to University of Florida Institutional Animal Care and Use Committee regulatory guidelines. Mice were housed in a stable environment with a 12-hour light\/dark cycle and access to food and water ad libitum. BALB\/c mice were procured from the Jackson Laboratory (Bar Harbor, MA). == Commercial TAK-779 Antibodies ==.<\/p>\n","protected":false},"excerpt":{"rendered":"

\ufeffNeuropathologically, LATE is defined and staged by virtue of the presence of intracytoplasmic deposits of TDP-43 within specific, reproducible areas of the neuraxis; early stages originate inclusions within medial limbic structures, while advanced stages show inclusions in cerebral neocortex. paraffin-embedded tissues, 2G11 and 2H1 robustly identified the classic inclusions of ALS and FTLD-TDP, and efficaciously […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[9],"tags":[],"class_list":["post-817","post","type-post","status-publish","format-standard","hentry","category-dna-ligases"],"_links":{"self":[{"href":"http:\/\/changingfaceofamerica.com\/index.php?rest_route=\/wp\/v2\/posts\/817","targetHints":{"allow":["GET"]}}],"collection":[{"href":"http:\/\/changingfaceofamerica.com\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"http:\/\/changingfaceofamerica.com\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"http:\/\/changingfaceofamerica.com\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"http:\/\/changingfaceofamerica.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=817"}],"version-history":[{"count":1,"href":"http:\/\/changingfaceofamerica.com\/index.php?rest_route=\/wp\/v2\/posts\/817\/revisions"}],"predecessor-version":[{"id":818,"href":"http:\/\/changingfaceofamerica.com\/index.php?rest_route=\/wp\/v2\/posts\/817\/revisions\/818"}],"wp:attachment":[{"href":"http:\/\/changingfaceofamerica.com\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=817"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"http:\/\/changingfaceofamerica.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=817"},{"taxonomy":"post_tag","embeddable":true,"href":"http:\/\/changingfaceofamerica.com\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=817"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}