Down syndrome (DS) is the most common genetic form of cognitive disability and is caused by trisomy of chromosome 21. Within chromosome 21 is the gene, amyloid precursor protein (APP). Proteolysis of APP into toxic and aggregate-prone, beta-amyloid fragments underlies the pathophysiology of Alzheimer's disease (AD). Individuals with DS develop the neuropathology that can be diagnosed as AD; however, the role of APP overexpression in this comorbidity is presently unclear. Here, we elucidated the mechanism of cell death induced by overexpression of wild type APP. Chinese hamster ovary cells transfected with a DsRed-APP fusion construct displayed caspase-3 activation and nuclear fragmentation indicative of apoptosis. APP-induced apoptosis was blocked by a pan-caspase inhibitor, (BOC), glutathione (GSH), or co-expression of Bcl-2. APP caused depletion of mitochondrial GSH, induced opening of the permeability transition pore, and triggered cytochrome c release. Each of these events was inhibited by GSH but was unaffected by BOC indicating that they were oxidative stress-dependent and upstream of caspases. We conclude that APP overexpression is sufficient to cause mitochondrial oxidative stress and intrinsic apoptosis. We are currently examining if a similar cell death pathway is induced by APP in neuronal cells. Our data are consistent with an increased expression of APP being a likely contributor to neuron death in DS. Thus, decreasing APP-induced oxidative stress and apoptosis may be beneficial in reducing the comorbid phenotype of DS patients afflicted with AD.
","abstract_html":"<p>Down syndrome (DS) is the most common genetic form of cognitive disability and is caused by trisomy of chromosome 21. Within chromosome 21 is the gene, amyloid precursor protein (APP). Proteolysis of APP into toxic and aggregate-prone, beta-amyloid fragments underlies the pathophysiology of Alzheimer's disease (AD). Individuals with DS develop the neuropathology that can be diagnosed as AD; however, the role of APP overexpression in this comorbidity is presently unclear. Here, we elucidated the mechanism of cell death induced by overexpression of wild type APP. Chinese hamster ovary cells transfected with a DsRed-APP fusion construct displayed caspase-3 activation and nuclear fragmentation indicative of apoptosis. APP-induced apoptosis was blocked by a pan-caspase inhibitor, (BOC), glutathione (GSH), or co-expression of Bcl-2. APP caused depletion of mitochondrial GSH, induced opening of the permeability transition pore, and triggered cytochrome c release. Each of these events was inhibited by GSH but was unaffected by BOC indicating that they were oxidative stress-dependent and upstream of caspases. We conclude that APP overexpression is sufficient to cause mitochondrial oxidative stress and intrinsic apoptosis. We are currently examining if a similar cell death pathway is induced by APP in neuronal cells. Our data are consistent with an increased expression of APP being a likely contributor to neuron death in DS. Thus, decreasing APP-induced oxidative stress and apoptosis may be beneficial in reducing the comorbid phenotype of DS patients afflicted with AD.</p>","abstract_has_math":false,"creators":["Bartley, Matthew G."],"institution":null,"degree_name":"M.S.","degree_level":"Masters Thesis","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Daniel A. Linseman, Ph.D.","Scott Barbee","David Patterson","Michelle Knowles"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2010,"date_issued":"2010-08-01T07:00:00Z","date_published":"2010-08-01T07:00:00Z","updated_at":"2026-07-24T02:03:12Z","subjects":["Down Syndrome","Amyloid precursor protein (APP)","Cell death","Animal research","Life Sciences","Neuroscience and Neurobiology"],"languages":["en"],"rights":["Copyright is held by the author. User is responsible for all copyright compliance.
"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.du.edu/etd/57","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Daniel A. Linseman, Ph.D.","Scott Barbee","David Patterson","Michelle Knowles"]},{"key":"dc:creator","label":"Author","values":["Bartley, Matthew G."]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2001-01-01T08:00:00Z"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Masters Thesis"]},{"key":"thesis:degree_name","label":"Degree Name","values":["M.S."]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Down Syndrome","Amyloid precursor protein (APP)","Cell death","Animal research","Life Sciences","Neuroscience and Neurobiology"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright is held by the author. User is responsible for all copyright compliance.
"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.du.edu/etd/57"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Down syndrome (DS) is the most common genetic form of cognitive disability and is caused by trisomy of chromosome 21. Within chromosome 21 is the gene, amyloid precursor protein (APP). Proteolysis of APP into toxic and aggregate-prone, beta-amyloid fragments underlies the pathophysiology of Alzheimer's disease (AD). Individuals with DS develop the neuropathology that can be diagnosed as AD; however, the role of APP overexpression in this comorbidity is presently unclear. Here, we elucidated the mechanism of cell death induced by overexpression of wild type APP. Chinese hamster ovary cells transfected with a DsRed-APP fusion construct displayed caspase-3 activation and nuclear fragmentation indicative of apoptosis. APP-induced apoptosis was blocked by a pan-caspase inhibitor, (BOC), glutathione (GSH), or co-expression of Bcl-2. APP caused depletion of mitochondrial GSH, induced opening of the permeability transition pore, and triggered cytochrome c release. Each of these events was inhibited by GSH but was unaffected by BOC indicating that they were oxidative stress-dependent and upstream of caspases. We conclude that APP overexpression is sufficient to cause mitochondrial oxidative stress and intrinsic apoptosis. We are currently examining if a similar cell death pathway is induced by APP in neuronal cells. Our data are consistent with an increased expression of APP being a likely contributor to neuron death in DS. Thus, decreasing APP-induced oxidative stress and apoptosis may be beneficial in reducing the comorbid phenotype of DS patients afflicted with AD.
"]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Overexpression of Amyloid Precursor Protein Induces Mitochondrial Oxidative Stress and Activates the Intrinsic Apoptosis Pathway"]}]}],"canonical_facts":{"dc:contributor":["Daniel A. Linseman, Ph.D.","Scott Barbee","David Patterson","Michelle Knowles"],"dc:creator":["Bartley, Matthew G."],"dc:date.available":["2001-01-01T08:00:00Z"],"dc:description.abstract":["Down syndrome (DS) is the most common genetic form of cognitive disability and is caused by trisomy of chromosome 21. Within chromosome 21 is the gene, amyloid precursor protein (APP). Proteolysis of APP into toxic and aggregate-prone, beta-amyloid fragments underlies the pathophysiology of Alzheimer's disease (AD). Individuals with DS develop the neuropathology that can be diagnosed as AD; however, the role of APP overexpression in this comorbidity is presently unclear. Here, we elucidated the mechanism of cell death induced by overexpression of wild type APP. Chinese hamster ovary cells transfected with a DsRed-APP fusion construct displayed caspase-3 activation and nuclear fragmentation indicative of apoptosis. APP-induced apoptosis was blocked by a pan-caspase inhibitor, (BOC), glutathione (GSH), or co-expression of Bcl-2. APP caused depletion of mitochondrial GSH, induced opening of the permeability transition pore, and triggered cytochrome c release. Each of these events was inhibited by GSH but was unaffected by BOC indicating that they were oxidative stress-dependent and upstream of caspases. We conclude that APP overexpression is sufficient to cause mitochondrial oxidative stress and intrinsic apoptosis. We are currently examining if a similar cell death pathway is induced by APP in neuronal cells. Our data are consistent with an increased expression of APP being a likely contributor to neuron death in DS. Thus, decreasing APP-induced oxidative stress and apoptosis may be beneficial in reducing the comorbid phenotype of DS patients afflicted with AD.
"],"dc:format":["application/pdf"],"dc:identifier":["https://digitalcommons.du.edu/etd/57"],"dc:language":["en"],"dc:rights":["Copyright is held by the author. User is responsible for all copyright compliance.
"],"dc:subject":["Down Syndrome","Amyloid precursor protein (APP)","Cell death","Animal research","Life Sciences","Neuroscience and Neurobiology"],"dc:title":["Overexpression of Amyloid Precursor Protein Induces Mitochondrial Oxidative Stress and Activates the Intrinsic Apoptosis Pathway"],"thesis:degree_level":["Masters Thesis"],"thesis:degree_name":["M.S."]},"updated_at":"2026-07-24T02:03:12Z"}