Mechanism Underlying Alzheimer-Like Damage in the Brain of Patients with Down Syndrome Elucidated by January 28, 2023 Life expectancy for individuals with Down syndrome has grown in recent decades, thanks in large part to progress in patient care and treatment. But with survival into the fifth and sixth decades of life now possible, increasing numbers of these individuals are affected by conditions linked to aging, among them impairments in thinking that are associated with the accumulation in the brain of atypical proteins better known for their involvement in Alzheimer\u2019s disease. \u201cThe decline in protein transport via the retromer system is a lot like a traffic jam, with the transporter stalling out and causing a major back-up in the clearance of pathologic tau proteins, leaving them to accumulate over time,\u201d explained Domenico Pratic\u00f2, MD, Scott Richards North Star Foundation Chair for Alzheimer\u2019s Research, Professor in the Department of Neural Sciences, Director of the Alzheimer\u2019s Center at Temple, and senior investigator on the new study. \u201cWe also found that a major factor underlying tau accumulation is diminished activity of the cathepsin-D enzyme, which resides within the retromer complex,\u201d Dr. Pratic\u00f2 added. Cathepsin-D normally acts like a pair of scissors, cutting up tau to facilitate its digestion and removal. The study, published online in the journal Annals of Neurology, is the first to connect reductions in retromer system efficiency and cathepsin-D activity to the accumulation of pathogenic tau in Down syndrome. The findings are significant because they suggest that Alzheimer-like changes are not strictly modulated by the extra copy of human chromosome 21 that is characteristic of Down syndrome. Even though the extra chromosome provides an additional copy of a gene known as amyloid precursor protein (APP), which increases the risk of amyloid plaque formation, not all Down syndrome patients develop dementia, implicating the involvement of factors beyond genetics. Dr. Pratic\u00f2 and colleagues first measured the extent of tau pathology in brain tissue from patients with Down syndrome and then assessed the relationship between the retromer core protein levels and the amount of pathologic tau protein in young and aged individuals with Down syndrome. They further compared the activity of cathepsin-D with the amount of tau pathology in the same individuals. The team\u2019s analyses uncovered an inverse relationship between the emergence of tau pathology in Down syndrome and the levels of retromer proteins and activity of cathepsin-D. Moreover, the team\u2019s observations suggest that reduced levels of retromer proteins in young Down syndrome subjects sets the stage for the development of tau pathology later in life. \u201cOverall, our data identify the retromer complex as a key regulator of pathogenic tau in Down syndrome, with evidence for the development of tau pathology at a relatively young age,\u201d Dr. Pratic\u00f2 said. The results also identify the retromer system as a promising new target for the treatment of Alzheimer\u2019s disease pathology in Down syndrome patients. Drugs that target the retromer system, such as small chaperones, have already been developed. In future work, Dr. Pratic\u00f2 and colleagues plan to explore these potential treatments in animal models that reproduce most of the aspects of Down syndrome observed in humans.. \u201cUsing these existing therapeutics, we want to see if it is possible to reverse amyloid plaque and pathological tau accumulation in animal models,\u201d Dr. Pratic\u00f2 added. \u201cIf we are successful, we will have created an exciting opportunity to explore treatments in human patients with Down syndrome.\u201d Other investigators who contributed to the new study include Mary Elizabeth Curtis and Tiffany Smith, Alzheimer\u2019s Center at Temple, Lewis Katz School of Medicine; and Daohai Yu, Department of Clinical Sciences, Lewis Katz School of Medicine. The study was funded in part by grants from the National Institutes of Health (AG055707 and AG056689). Domenico Pratic\u00f2, MD, is the Scott Richards North Star Charitable Foundation Chair for Alzheimer\u2019s Research, Professor and Director of the Alzheimer\u2019s Center at Temple, and Professor of Pharmacology at the Lewis Katz School of Medicine at Temple University You can find out more information on Dr. Domenico Pratico’s research papers here. Connect with Dr. Domenico Pratico on LinkedIn, Facebook, Twitter & Instagram Follow Dr Domenico Pratico‘s lab website here: Pratico Lab<\/p>\n","protected":false},"author":1,"featured_media":1609,"comment_status":"open","ping_status":"open","sticky":false,"template":"elementor_header_footer","format":"standard","meta":{"ocean_post_layout":"","ocean_both_sidebars_style":"","ocean_both_sidebars_content_width":0,"ocean_both_sidebars_sidebars_width":0,"ocean_sidebar":"","ocean_second_sidebar":"","ocean_disable_margins":"enable","ocean_add_body_class":"","ocean_shortcode_before_top_bar":"","ocean_shortcode_after_top_bar":"","ocean_shortcode_before_header":"","ocean_shortcode_after_header":"","ocean_has_shortcode":"","ocean_shortcode_after_title":"","ocean_shortcode_before_footer_widgets":"","ocean_shortcode_after_footer_widgets":"","ocean_shortcode_before_footer_bottom":"","ocean_shortcode_after_footer_bottom":"","ocean_display_top_bar":"default","ocean_display_header":"default","ocean_header_style":"","ocean_center_header_left_menu":"","ocean_custom_header_template":"","ocean_custom_logo":0,"ocean_custom_retina_logo":0,"ocean_custom_logo_max_width":0,"ocean_custom_logo_tablet_max_width":0,"ocean_custom_logo_mobile_max_width":0,"ocean_custom_logo_max_height":0,"ocean_custom_logo_tablet_max_height":0,"ocean_custom_logo_mobile_max_height":0,"ocean_header_custom_menu":"","ocean_menu_typo_font_family":"","ocean_menu_typo_font_subset":"","ocean_menu_typo_font_size":0,"ocean_menu_typo_font_size_tablet":0,"ocean_menu_typo_font_size_mobile":0,"ocean_menu_typo_font_size_unit":"px","ocean_menu_typo_font_weight":"","ocean_menu_typo_font_weight_tablet":"","ocean_menu_typo_font_weight_mobile":"","ocean_menu_typo_transform":"","ocean_menu_typo_transform_tablet":"","ocean_menu_typo_transform_mobile":"","ocean_menu_typo_line_height":0,"ocean_menu_typo_line_height_tablet":0,"ocean_menu_typo_line_height_mobile":0,"ocean_menu_typo_line_height_unit":"","ocean_menu_typo_spacing":0,"ocean_menu_typo_spacing_tablet":0,"ocean_menu_typo_spacing_mobile":0,"ocean_menu_typo_spacing_unit":"","ocean_menu_link_color":"","ocean_menu_link_color_hover":"","ocean_menu_link_color_active":"","ocean_menu_link_background":"","ocean_menu_link_hover_background":"","ocean_menu_link_active_background":"","ocean_menu_social_links_bg":"","ocean_menu_social_hover_links_bg":"","ocean_menu_social_links_color":"","ocean_menu_social_hover_links_color":"","ocean_disable_title":"default","ocean_disable_heading":"default","ocean_post_title":"","ocean_post_subheading":"","ocean_post_title_style":"","ocean_post_title_background_color":"","ocean_post_title_background":0,"ocean_post_title_bg_image_position":"","ocean_post_title_bg_image_attachment":"","ocean_post_title_bg_image_repeat":"","ocean_post_title_bg_image_size":"","ocean_post_title_height":0,"ocean_post_title_bg_overlay":0.5,"ocean_post_title_bg_overlay_color":"","ocean_disable_breadcrumbs":"default","ocean_breadcrumbs_color":"","ocean_breadcrumbs_separator_color":"","ocean_breadcrumbs_links_color":"","ocean_breadcrumbs_links_hover_color":"","ocean_display_footer_widgets":"default","ocean_display_footer_bottom":"default","ocean_custom_footer_template":"","ocean_post_oembed":"","ocean_post_self_hosted_media":"","ocean_post_video_embed":"","ocean_link_format":"","ocean_link_format_target":"self","ocean_quote_format":"","ocean_quote_format_link":"post","ocean_gallery_link_images":"on","ocean_gallery_id":[],"footnotes":""},"categories":[1],"tags":[],"class_list":["post-1608","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-uncategorized","entry","has-media"],"yoast_head":"\n