{"id":308,"date":"2017-03-02T02:12:22","date_gmt":"2017-03-02T02:12:22","guid":{"rendered":"https:\/\/www.mybiosource.com\/learn\/?p=308"},"modified":"2023-03-06T18:18:19","modified_gmt":"2023-03-06T18:18:19","slug":"alzheimers-disease-do-we-need-a-traffic-cop-to-prevent-pathology","status":"publish","type":"post","link":"https:\/\/www.mybiosource.com\/learn\/alzheimers-disease-do-we-need-a-traffic-cop-to-prevent-pathology\/","title":{"rendered":"Alzheimer\u2019s Disease: Do We Need A Traffic Cop To Prevent Pathology?"},"content":{"rendered":"

Table of Contents<\/strong><\/span><\/h2>\n

1. Introduction: Alzheimer\u2019s disease (AD) and its impact<\/strong>
\n2. Neuronal trafficking and its role in AD development<\/strong>
\n3. Dysfunctional neuronal trafficking <\/strong>
\n4. Key protein expression changes and mutations associated with AD<\/strong>
\n5. The role of ApoE and clathrin in AD<\/strong>
\n6. Abnormal activation of Rab5 in AD<\/strong>
\n7. Impact of trafficking dysfunction on neurons<\/strong>
\n8. Conclusion: Implications for future research on AD.<\/strong><\/p>\n

\n

Alzheimer\u2019s disease<\/span> (AD<\/span>) is turning out to be one of the greatest challenges to lengthening our lifespan. The costs to our healthcare industry are staggering and the personal costs have no price tag. Although the contributions from other CNS<\/span> cell types, like reactive astrocytes<\/span> and inflammatory microglia<\/span>, are not to be discounted; recently published work by scientists in the UCSD Neuroscience<\/span> Department confirm a 20-year old observation at a molecular level, that dysfunctional neuronal<\/span> trafficking is associated with the development of AD<\/span>.<\/p>\n

\"Statistic:<\/a>Find more statistics at Statista<\/a><\/strong><\/p>\n

The movement of materials from outside a cell or transport of synthesized proteins within a cell is generally termed \u201ccellular trafficking\u201d. Metaphorically, these processes represent a complex folk dance, with rapidly changing partners, rhythm and tempo changes and intricate steps. In diseases<\/a> like AD<\/span>, these steps can be blocked, missing \u201cdance partners\u201d or have the music change direction. Cataldo et al., used microscopy to visualize one of these dance steps in pyramidal neurons<\/span> in 1997 1. His group found that an early vesicle<\/span> in cellular trafficking, the endosomal compartment, is enlarged in AD<\/span> neurons compared to non-disease controls. At the time, endocytotic machinery was just being elucidated and little was known about the functions and signaling<\/span> properties of these compartments. In subsequent years, we have gained a greater understanding of the processes from stimulation of membrane receptors<\/span>, to early intracellular<\/span> signaling<\/span> cascades, to the function of endosomes<\/span> as signaling<\/span> platforms, recycling compartments and sorting compartments.<\/p>\n

Many of these key trafficking steps have AD<\/span> associated protein expression<\/span> changes or newly recognized mutations<\/span>. Early in the 1990\u2019s, the first major variant clearly associated with the development of AD<\/span> was identified: ApoE4<\/span>. In the CNS<\/span>, ApoE<\/span> uptake is through clathrin<\/span> \u2013 mediated endocytosis<\/span> by LRP1<\/span>, which has decreased expression<\/span> in AD<\/span> patients. The clathrin<\/span> coat is critical for later fusion with endosomes<\/span>. PICALM, with known highly penetrant AD<\/span> associated mutations<\/span>, recruits clathrin<\/span> to the membrane. ApoE<\/span> further traffics to early endosomes<\/span> and can take one of several subsequent routes through late endosomes<\/span> to golgi stacks or directly to lysosomes for degradation. The current study focuses in on early endosomes<\/span>, marked by the small molecular switch Rab5. When Rab5 is constitutively \u201con\u201d, endosomes<\/span> become enlarged since cargo isn\u2019t handed off in a precisely timed fashion. The researchers at UCSD have found that Rab5 is abnormally activated in AD<\/span>, causing early signaling<\/span> and trafficking dysfunction, just one more piece in the trafficking puzzle 2. With cargo movement being blocked or hindered in this early transition, neurons are deprived of nuclear translocation<\/span> for transcriptional regulation<\/span>, cargo transport of cellular nutrients and required recycling or degradation of membrane receptors<\/span>.<\/p>\n

1. Cataldo AM, Barnett JL, Pieroni C, & Nixon RA (1997) Increased neuronal<\/span> endocytosis<\/span> and protease<\/span> delivery to early endosomes<\/span> in sporadic Alzheimer\u2019s disease<\/span>: neuropathologic evidence for a mechanism of increased beta-amyloidogenesis. J Neurosci 17(16):6142-6151.
\n2. Xu W, et al. (2016) Amyloid<\/span> precursor protein-mediated endocytic pathway<\/span> disruption induces axonal<\/span> dysfunction and neurodegeneration<\/span>. J Clin Invest.<\/p>\n","protected":false},"excerpt":{"rendered":"

Table of Contents 1. Introduction: Alzheimer\u2019s disease (AD) and its impact 2. Neuronal trafficking and its role in AD development 3. Dysfunctional neuronal trafficking 4. Key protein expression changes and mutations associated with AD 5. The role of ApoE and clathrin in AD 6. Abnormal activation of Rab5 in AD 7. Impact of trafficking dysfunction […]<\/p>\n","protected":false},"author":3,"featured_media":309,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_et_pb_use_builder":"","_et_pb_old_content":"","_et_gb_content_width":"","footnotes":""},"categories":[3],"tags":[],"class_list":["post-308","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-conditions"],"_links":{"self":[{"href":"https:\/\/www.mybiosource.com\/learn\/wp-json\/wp\/v2\/posts\/308","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.mybiosource.com\/learn\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.mybiosource.com\/learn\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.mybiosource.com\/learn\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/www.mybiosource.com\/learn\/wp-json\/wp\/v2\/comments?post=308"}],"version-history":[{"count":0,"href":"https:\/\/www.mybiosource.com\/learn\/wp-json\/wp\/v2\/posts\/308\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.mybiosource.com\/learn\/wp-json\/wp\/v2\/media\/309"}],"wp:attachment":[{"href":"https:\/\/www.mybiosource.com\/learn\/wp-json\/wp\/v2\/media?parent=308"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.mybiosource.com\/learn\/wp-json\/wp\/v2\/categories?post=308"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.mybiosource.com\/learn\/wp-json\/wp\/v2\/tags?post=308"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}