BEGIN:VCALENDAR VERSION:2.0 PRODID:-//jEvents 2.0 for Joomla//EN CALSCALE:GREGORIAN METHOD:PUBLISH BEGIN:VEVENT UID:12377b77743f90714468ed2c80b62c56 CATEGORIES:Colloquium CREATED:20220830T153720 SUMMARY:Professor Ying Xu, Rutgers New Jersey Medical School DESCRIPTION:
Defining phosphodiesterase 2A directed mitochondrial dysfunctio n in Alzheimer’s disease
Mitoch ondrial dysfunction is an early pathological hallmark of Alzheimer’s diseas e (AD) that plays a role in mild cognitive impairment (MCI) and dementia. R ecent studies in animal models of AD and brains from patients with AD sugge st that both amyloid precursor protein (APP) and amyloid-? (A?) are localiz ed to mitochondria, while Tau accumulation contributes to mitochondrial def ects including excessive mitochondrial fragmentation and abnormal mitochond rial distribution. These suggest that regulation of defective mitochondria can be a promising therapeutic approach for early stages of AD. Phosphodies terase 2A (PDE2A) is the most prevalent of PDEs broadly expressed in fronta l and temporal cortex, and hippocampus, brain regions involved in cognitive impairment, particularly at early stages of AD. PDE2A is encoded by three isoforms, PDE2A1, 2A2 and 2A3. The unique N-terminus of the PDE2A2 isoform contains a 17 amino acid sequence that leads to its mitochondrial localizat ion, where it is the primary regulator of cyclic nucleotide signaling; PDE2 A1/3 are not found in mitochondria. The co-localization of PDE2A2 with syna ptophysin in pyramidal neurons of hippocampus places it in a key position t o regulate altered synaptic plasticity and memory impairment associated wit h AD; thus, this isoform represents a promising drug target. To date, devel opment of PDE2A inhibitors has not progressed due to issues of toxicity and tolerability. Specifically targeting the mitochondrial PDE2A2 isoform rela tive to the cytosolic PDE2A1 and PDE2A3 isoforms could lead to reduced toxi city. To explore this possibility, we will use forebrain specific PDE2A kno ckout and PDE2A2 functional knockout mouse models to address target validat ion. Novel mitochondria-targeting conjugates with high affinity and efficac y for inhibiting PDE2A will be identified by in vitro and in vivo experimen ts (Aim 2). The result of this work provides the rationale for future resea rch to develop selective PDE2A2 inhibitors with good drug-like properties, low toxicity, high tolerability, and strong potential for the treatment of AD related dementias.
Hosted by Professor KiBum Lee
< p>Hybrid seminar: On-site location is CCB-1303; for Z oom meeting information, please contact Loretta Lupo atDefining phosphodiesterase 2A directed mitochondrial dysfunction in Alzheimer’s disease
Mitochondrial dysfunction is an early pathological hallm ark of Alzheimer’s disease (AD) that plays a role in mild cognitive impairm ent (MCI) and dementia. Recent studies in animal models of AD and brains fr om patients with AD suggest that both amyloid precursor protein (APP) and a myloid-? (A?) are localized to mitochondria, while Tau accumulation contrib utes to mitochondrial defects including excessive mitochondrial fragmentati on and abnormal mitochondrial distribution. These suggest that regulation o f defective mitochondria can be a promising therapeutic approach for early stages of AD. Phosphodiesterase 2A (PDE2A) is the most prevalent of PDEs br oadly expressed in frontal and temporal cortex, and hippocampus, brain regi ons involved in cognitive impairment, particularly at early stages of AD. P DE2A is encoded by three isoforms, PDE2A1, 2A2 and 2A3. The unique N-termin us of the PDE2A2 isoform contains a 17 amino acid sequence that leads to it s mitochondrial localization, where it is the primary regulator of cyclic n ucleotide signaling; PDE2A1/3 are not found in mitochondria. The co-localiz ation of PDE2A2 with synaptophysin in pyramidal neurons of hippocampus plac es it in a key position to regulate altered synaptic plasticity and memory impairment associated with AD; thus, this isoform represents a promising dr ug target. To date, development of PDE2A inhibitors has not progressed due to issues of toxicity and tolerability. Specifically targeting the mitochon drial PDE2A2 isoform relative to the cytosolic PDE2A1 and PDE2A3 isoforms c ould lead to reduced toxicity. To explore this possibility, we will use for ebrain specific PDE2A knockout and PDE2A2 functional knockout mouse models to address target validation. Novel mitochondria-targeting conjugates with high affinity and efficacy for inhibiting PDE2A will be identified by in vi tro and in vivo experiments (Aim 2). The result of this work provides the r ationale for future research to develop selective PDE2A2 inhibitors with go od drug-like properties, low toxicity, high tolerability, and strong potent ial for the treatment of AD related dementias.
Hosted by Professor KiBum Lee
Hybrid seminar: On-site lo
cation is CCB-1303; for Zoom meeting information, please contact Loretta Lu
po at <
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