NYU Technology Opportunities & Ventures’ Post

This is another case of interpreting data on Alzheimer's disease through the toxic-proteins prism. Lower γ-secretase activity among PSEN1 mutation carriers is associated with an earlier onset of Alzheimer's disease, faster progression, more brain atrophy, and lower Aβ42 and Aβ42/Aβ40 ratios. 𝐀𝐮𝐭𝐡𝐨𝐫𝐬' 𝐢𝐦𝐩𝐥𝐢𝐜𝐚𝐭𝐢𝐨𝐧𝐬: "These findings support targeting γ-secretase as a therapeutic approach via γ-secretase modulation" (which lowers Aβ42). https://lnkd.in/eYxupA3Z Huh? This study aimed to understand how clinical differences in autosomal dominant Alzheimer's disease can be partly explained by varying effects of PSEN1 variants on γ-secretase activity. However, under our current paradigm, even low-activity proteins are toxic. “Previous work suggests some pathogenic PSEN1 variants might not substantially alter the absolute amounts of Aβ42 production”. But most PSEN1 mutations 𝐫𝐞𝐝𝐮𝐜𝐞 𝐀β𝟒𝟐 𝐚𝐧𝐝 𝐀β𝟒𝟎 𝐥𝐞𝐯𝐞𝐥𝐬. https://lnkd.in/ejZhbXH6 “Previous studies have suggested that an increase in aggregation-prone amyloid β fragments (e.g., Aβ42) is a crucial initiating pathogenic event” in sporadic and autosomal dominant Alzheimer’s. Yet 𝐝𝐞𝐜𝐫𝐞𝐚𝐬𝐞𝐬 𝐢𝐧 𝐀β𝟒𝟐 𝐥𝐞𝐯𝐞𝐥𝐬 begin decades before onset. https://lnkd.in/e4T_ruh8 𝐀𝐥𝐭𝐞𝐫𝐧𝐚𝐭𝐢𝐯𝐞 𝐢𝐦𝐩𝐥𝐢𝐜𝐚𝐭𝐢𝐨𝐧𝐬: PSEN1 mutations cause γ-secretase loss of function, reducing the production of its substrates, including Aβ42. We should focus on rescuing these functions, not decreasing them. #AlzheimersDisease #Neuroscience #Genetics #MedicalResearch #Therapeutics

#neurodegenerativedisease #microglia #monocyte Patient-specific monocyte-derived microglia as a screening tool for neurodegenerative diseases https://lnkd.in/dBW2RrQH Hazel Quek The University of Queensland QIMR Berghofer Medical Research Institute Microglia, the main driver of neuroinflammation, play a central role in the initiation and exacerbation of various neurodegenerative diseases and are now considered a promising therapeutic target. Previous studies on in vitro human microglia and in vivo rodent models lacked scalability, consistency, or physiological relevance, which deterred successful therapeutic outcomes for the past decade. Here we review human blood monocyte-derived microglia-like cells as a robust and consistent approach to generate a patient-specific microglia-like model that can be used in extensive cohort studies for drug testing. We will highlight the strength and applicability of human blood monocyte-derived microglia-like cells to increase translational outcomes by reviewing the advantages of human blood monocyte-derived microglia-like cells in addressing patient heterogeneity and stratification, the basis of personalized medicine.

📃Scientific paper: LRRK2 mediates haloperidol-induced changes in indirect pathway striatal projection neurons Abstract: Haloperidol is used to manage psychotic symptoms in several neurological disorders through mechanisms that involve antagonism of dopamine D2 receptors that are highly expressed in the striatum. Significant side effects of haloperidol, known as extrapyramidal symptoms, lead to motor deficits similar to those seen in Parkinson's disease and present a major challenge in clinical settings. The underlying molecular mechanisms responsible for these side effects remain poorly understood. Parkinson's disease-associated LRRK2 kinase has an important role in striatal physiology and a known link to dopamine D2 receptor signaling. Here, we systematically explore convergent signaling of haloperidol and LRRK2 through pharmacological or genetic inhibition of LRRK2 kinase, as well as knock-in mouse models expressing pathogenic mutant LRRK2 with increased kinase activity. Behavioral assays show that LRRK2 kinase inhibition ameliorates haloperidol-induced motor changes in mice. A combination of electrophysiological and anatomical approaches reveals that LRRK2 kinase inhibition interferes with haloperidol-induced changes, specifically in striatal neurons of the indirect pathway. Proteomic studies and targeted intracellular pathway analyses demonstrate that haloperidol induces a similar pattern of intracellular signaling as increased LRRK2 kinase activity. Our study suggests that LRRK2 kinase plays a key role in striatal dopamine D2 receptor signaling underlying the undesirable motor s... Continued on ES/IODE ➡️ https://etcse.fr/oLQ ------- If you find this interesting, feel free to follow, comment and share. We need your help to enhance our visibility, so that our platform continues to serve you.

📃Scientific paper: p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease Abstract: Background Parkinson’s disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), accompanied by accumulation of α-synuclein, chronic neuroinflammation and autophagy dysfunction. Previous studies suggested that misfolded α-synuclein induces the inflammatory response and autophagy dysfunction in microglial cells. The NLRP3 inflammasome signaling pathway plays a crucial role in the neuroinflammatory process in the central nervous system. However, the relationship between autophagy deficiency and NLRP3 activation induced by α-synuclein accumulation is not well understood. Methods Through immunoblotting, immunocytochemistry, immunofluorescence, flow cytometry, ELISA and behavioral tests, we investigated the role of p38-TFEB-NLRP3 signaling pathways on neuroinflammation in the α-synuclein A53T PD models. Results Our results showed that increased protein levels of NLRP3, ASC, and caspase-1 in the α-synuclein A53T PD models. P38 is activated by overexpression of α-synuclein A53T mutant, which inhibited the master transcriptional activator of autophagy TFEB. And we found that NLRP3 was degraded by chaperone-mediated autophagy (CMA) in microglial cells. Furthermore, p38-TFEB pathways inhibited CMA-mediated NLRP3 degradation in Parkinson's disease. Inhibition of p38 had a protective effect on Parkinson's disease model via suppressing the activation of NLRP3 inflammasome pathway. Moreover, both p38 inhibitor SB203580 a... Continued on ES/IODE ➡️ https://etcse.fr/EUp ------- If you find this interesting, feel free to follow, comment and share. We need your help to enhance our visibility, so that our platform continues to serve you.

📃Scientific paper: LRRK2 mediates haloperidol-induced changes in indirect pathway striatal projection neurons Abstract: Haloperidol is used to manage psychotic symptoms in several neurological disorders through mechanisms that involve antagonism of dopamine D2 receptors that are highly expressed in the striatum. Significant side effects of haloperidol, known as extrapyramidal symptoms, lead to motor deficits similar to those seen in Parkinson's disease and present a major challenge in clinical settings. The underlying molecular mechanisms responsible for these side effects remain poorly understood. Parkinson's disease-associated LRRK2 kinase has an important role in striatal physiology and a known link to dopamine D2 receptor signaling. Here, we systematically explore convergent signaling of haloperidol and LRRK2 through pharmacological or genetic inhibition of LRRK2 kinase, as well as knock-in mouse models expressing pathogenic mutant LRRK2 with increased kinase activity. Behavioral assays show that LRRK2 kinase inhibition ameliorates haloperidol-induced motor changes in mice. A combination of electrophysiological and anatomical approaches reveals that LRRK2 kinase inhibition interferes with haloperidol-induced changes, specifically in striatal neurons of the indirect pathway. Proteomic studies and targeted intracellular pathway analyses demonstrate that haloperidol induces a similar pattern of intracellular signaling as increased LRRK2 kinase activity. Our study suggests that LRRK2 kinase plays a key role in striatal dopamine D2 receptor signaling underlying the undesirable motor s... Continued on ES/IODE ➡️ https://etcse.fr/oLQ ------- If you find this interesting, feel free to follow, comment and share. We need your help to enhance our visibility, so that our platform continues to serve you.

𝗚𝗧-𝟬𝟮𝟮𝟴𝟳: 𝗔 𝗖𝗹𝗶𝗻𝗶𝗰𝗮𝗹-𝗦𝘁𝗮𝗴𝗲 𝗚𝗖𝗮𝘀𝗲 𝗘𝗻𝗵𝗮𝗻𝗰𝗲𝗿 𝗳𝗼𝗿 𝗣𝗮𝗿𝗸𝗶𝗻𝘀𝗼𝗻’𝘀 𝗗𝗶𝘀𝗲𝗮𝘀𝗲 👉 Gain Therapeutics has developed an experimental drug called GT-02287 for the treatment of Parkinson’s disease associated with mutations in the GBA1 gene. 👉 GT-02287 is currently in phase 1 clinical trials. It targets an enzyme called glucocerebrosidase (or GCase), which is found in neurons’ lysosomes. Certain mutations in the GBA1 gene encoding GCase prevent the enzyme from functioning properly. This dysfunction is associated with Parkinson’s disease. 👉 GT-02287, a brain-penetrant small molecule, is an allosteric protein modulator that aims to restore the function of GCase.   According to the company, in preclinical models of Parkinson's disease , GT-02287 restored GCase enzymatic function, reduced aggregated α-synuclein, neuroinflammation and neuronal death, and improved motor function and cognitive performance. #parkinson #neurology #genemutation #gene #lysosome #brain #neuron #biology #medicine #neurodegenerative #clinicaltrial

Short-hairpin RNAs (#shRNA), targeting knockdown of specific genes, hold enormous promise for precision-based therapeutics to treat numerous neurodegenerative disorders. Cognigenics has advanced an RNA-based therapy, COG-201, that can enhance memory and reduce anxiety in animal models by targeting the serotonin 5-HT2A receptor. Scientists found that decreasing this receptor’s expression led to improved cognitive function and reduced anxiety-like behaviors in mice and rats. They designed shRNA to knockdown the human HTR2A gene in vitro using iPSC-differentiated neurons. Multi-electrode array (MEA) results showed that the knockdown of the 5HT-2A mRNA and receptor protein led to a decrease in spontaneous electrical activity. The demonstration of a non-invasive shRNA delivery platform that can bypass the blood–brain barrier (BBB) has broad implications for treating numerous neurological mental disorders. Specifically, targeting the HTR2A gene presents a novel therapeutic approach for treating chronic anxiety and age-related cognitive decline. https://lnkd.in/eRWw9kiH #RNA #AAV #anxiety #anxietydisorders #innovation #BBB #bloodbrainbarrier #drugdelivery #intranasal #genetherapy #geneediting #medicine #technology #nanotechnology #science

📃Scientific paper: p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease Abstract: Background Parkinson’s disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), accompanied by accumulation of α-synuclein, chronic neuroinflammation and autophagy dysfunction. Previous studies suggested that misfolded α-synuclein induces the inflammatory response and autophagy dysfunction in microglial cells. The NLRP3 inflammasome signaling pathway plays a crucial role in the neuroinflammatory process in the central nervous system. However, the relationship between autophagy deficiency and NLRP3 activation induced by α-synuclein accumulation is not well understood. Methods Through immunoblotting, immunocytochemistry, immunofluorescence, flow cytometry, ELISA and behavioral tests, we investigated the role of p38-TFEB-NLRP3 signaling pathways on neuroinflammation in the α-synuclein A53T PD models. Results Our results showed that increased protein levels of NLRP3, ASC, and caspase-1 in the α-synuclein A53T PD models. P38 is activated by overexpression of α-synuclein A53T mutant, which inhibited the master transcriptional activator of autophagy TFEB. And we found that NLRP3 was degraded by chaperone-mediated autophagy (CMA) in microglial cells. Furthermore, p38-TFEB pathways inhibited CMA-mediated NLRP3 degradation in Parkinson's disease. Inhibition of p38 had a protective effect on Parkinson's disease model via suppressing the activation of NLRP3 inflammasome pathway. Moreover, both p38 inhibitor SB203580 a... Continued on ES/IODE ➡️ https://etcse.fr/EUp ------- If you find this interesting, feel free to follow, comment and share. We need your help to enhance our visibility, so that our platform continues to serve you.

📃Scientific paper: LRRK2 mediates haloperidol-induced changes in indirect pathway striatal projection neurons Abstract: Haloperidol is used to manage psychotic symptoms in several neurological disorders through mechanisms that involve antagonism of dopamine D2 receptors that are highly expressed in the striatum. Significant side effects of haloperidol, known as extrapyramidal symptoms, lead to motor deficits similar to those seen in Parkinson's disease and present a major challenge in clinical settings. The underlying molecular mechanisms responsible for these side effects remain poorly understood. Parkinson's disease-associated LRRK2 kinase has an important role in striatal physiology and a known link to dopamine D2 receptor signaling. Here, we systematically explore convergent signaling of haloperidol and LRRK2 through pharmacological or genetic inhibition of LRRK2 kinase, as well as knock-in mouse models expressing pathogenic mutant LRRK2 with increased kinase activity. Behavioral assays show that LRRK2 kinase inhibition ameliorates haloperidol-induced motor changes in mice. A combination of electrophysiological and anatomical approaches reveals that LRRK2 kinase inhibition interferes with haloperidol-induced changes, specifically in striatal neurons of the indirect pathway. Proteomic studies and targeted intracellular pathway analyses demonstrate that haloperidol induces a similar pattern of intracellular signaling as increased LRRK2 kinase activity. Our study suggests that LRRK2 kinase plays a key role in striatal dopamine D2 receptor signaling underlying the undesirable motor s... Continued on ES/IODE ➡️ https://etcse.fr/oLQ ------- If you find this interesting, feel free to follow, comment and share. We need your help to enhance our visibility, so that our platform continues to serve you.

📃Scientific paper: LRRK2 mediates haloperidol-induced changes in indirect pathway striatal projection neurons Abstract: Haloperidol is used to manage psychotic symptoms in several neurological disorders through mechanisms that involve antagonism of dopamine D2 receptors that are highly expressed in the striatum. Significant side effects of haloperidol, known as extrapyramidal symptoms, lead to motor deficits similar to those seen in Parkinson's disease and present a major challenge in clinical settings. The underlying molecular mechanisms responsible for these side effects remain poorly understood. Parkinson's disease-associated LRRK2 kinase has an important role in striatal physiology and a known link to dopamine D2 receptor signaling. Here, we systematically explore convergent signaling of haloperidol and LRRK2 through pharmacological or genetic inhibition of LRRK2 kinase, as well as knock-in mouse models expressing pathogenic mutant LRRK2 with increased kinase activity. Behavioral assays show that LRRK2 kinase inhibition ameliorates haloperidol-induced motor changes in mice. A combination of electrophysiological and anatomical approaches reveals that LRRK2 kinase inhibition interferes with haloperidol-induced changes, specifically in striatal neurons of the indirect pathway. Proteomic studies and targeted intracellular pathway analyses demonstrate that haloperidol induces a similar pattern of intracellular signaling as increased LRRK2 kinase activity. Our study suggests that LRRK2 kinase plays a key role in striatal dopamine D2 receptor signaling underlying the undesirable motor s... Continued on ES/IODE ➡️ https://etcse.fr/oLQ ------- If you find this interesting, feel free to follow, comment and share. We need your help to enhance our visibility, so that our platform continues to serve you.