Caspian J Neurol Sci (CJNS)’s Post

Alternative splicing of the Insulin Receptor (IR) gene generates two isoforms, IRA and IRB, by comparison. Indeed, IRB differs from IRA by the inclusion of exon 11 which encodes a 12-amino acid sequence at jthe C-terminusof the IR α-subunit. The IR isoforms show different functional features and most significantly here a greatly reduced affinity of insulin for the A variant compared with the B form results in relative insulin resistance: a fact that may have significant implications in the role of role of cerebral blood vessels that may lead to a “comprehensive model of brain insulin dysfunction in Alzheimer Disease and Related Disorders. So in this scientific commentary the authors Timothy M. Hughes and Suzanne Craft (Dept. of Internal Medicine, Wake Forest Univ. School of Med., Winston-Salem, NC, USA) refer to ‘Cerebrovascular insulin receptors are defective in Alzheimer’s disease’ by Leclerc et al. (https://lnkd.in/gpCGnrre).

#neurodegenerativedisorders #Tau #synapses #cells #therapy Therapies for Tau-associated neurodegenerative disorders: targeting molecules, synapses, and cells https://lnkd.in/g-KWE4q3 University of Cambridge Advances in experimental and computational technologies continue to grow rapidly to provide novel avenues for the treatment of neurodegenerative disorders. Despite this, there remain only a handful of drugs that have shown success in late-stage clinical trials for Tau-associated neurodegenerative disorders. The most commonly prescribed treatments are symptomatic treatments such as cholinesterase inhibitors and N-methyl-D-aspartate receptor blockers that were approved for use in Alzheimer’s disease. This mini-review will highlight five key avenues of academic and industrial research for identifying therapeutic strategies to treat Tau-associated neurodegenerative disorders. These avenues include investigating (1) the broad class of chemicals termed “small molecules”; (2) adaptive immunity through both passive and active antibody treatments; (3) innate immunity with an emphasis on microglial modulation; (4) synaptic compartments with the view that Tau-associated neurodegenerative disorders are synaptopathies. Although this mini-review will focus on Alzheimer’s disease due to its prevalence, it will also argue the need to target other tauopathies, as through understanding Alzheimer’s disease as a Tau-associated neurodegenerative disorder, we may be able to generalize treatment options. For this reason, added detail linking back specifically to Tau protein as a direct therapeutic target will be added to each topic.

#Alzheimer #apolipoproteinEisoforms #amyloidbeta Impact of apolipoprotein E isoforms on sporadic Alzheimer’s disease: beyond the role of amyloid beta https://lnkd.in/gwYkm4RY Università degli Studi di Bari The impact of apolipoprotein E (ApoE) isoforms on sporadic Alzheimer’s disease has long been studied; however, the influences of apolipoprotein E gene (APOE) on healthy and pathological human brains are not fully understood. The objectives of the present mini-review were to describe classical and new roles of various ApoE isoforms in Alzheimer’s disease pathophysiology beyond the deposition of amyloid-beta and to establish a functional link between APOE, brain function, and memory, from a molecular to a clinical level. APOE genotype also exerted a heterogeneous effect on clinical Alzheimer’s disease phenotype and its outcomes. Not only in learning and memory but also in neuropsychiatric symptoms that occur in a premorbid condition. Clarifying the relationships between Alzheimer’s disease-related pathology with neuropsychiatric symptoms, particularly suicidal ideation in Alzheimer’s disease patients, may be useful for elucidating also the underlying pathophysiological process and its prognosis. Also, the effects of anti-amyloid-beta drugs, recently approved for the treatment of Alzheimer’s disease, could be influenced by the APOE genotype.

Restoring hippocampal glucose metabolism rescues cognition across Alzheimer’s disease (AD) pathologies Inhibition of indoleamine-2,3-dioxygenase 1 (IDO1), which metabolizes tryptophan to kynurenine (KYN), rescues hippocampal memory function in mouse preclinical models of AD by restoring astrocyte metabolism. https://lnkd.in/d5kr3Jfe

Our Phase I/II clinical trial NTIRTT1, investigating the use of NTI164 in female Rett Syndrome patients, has been extended. All fourteen participants will receive NTI164 treatment for 52 weeks under the extension phase, with clearance from the Human Research Ethics Committee. The trial aims to assess the efficacy of NTI164, a cannabinoid drug therapy, in treating Rett Syndrome, a rare genetic neurological disorder predominantly affecting girls. Rett Syndrome results from mutations in the MECP2 gene, impacting brain development and function. We anticipate the results of the NTIRTT1 clinical trial in late Q1 to early Q2 CY2024.   Executive Director, Dr. Thomas Duthy, said “The extension phase to 52 weeks of daily oral treatment with NTI164 was approved by Westmead’s Human Research Ethics Committee under the clinical trial protocol. It is certainly pleasing that under the supervision and care of Associate Professor Carolyn Ellaway at The Children's Hospital at Westmead that all patients and their families have elected to continue treatment with NTI164 for a period of one year. We eagerly await the clinical findings from this world-first cannabinoid drug therapy trial in Rett Syndrome over the coming weeks.” Read the full ASX Announcement here: https://lnkd.in/g4EsD2_U #Neurotech #NTI #ASX #ASXNews #Healthcare #Neurology #RettSyndrome #neurologicalresearch 

Paul Hyslop, from ARKLEY BIOTEK LLC Indianapolis, details an ongoing specific research approach to identify, characterize, and validate physiologically relevant neuronal targets of #H2O2 in designing therapeutics for #neurodegenerative disease progression The societal impact of #dementia resulting from the major neurodegenerative diseases such as #Alzheimer’s presents a growing and significant unmet medical need. (1) Various cellular #metabolic and structural deficits, neuroinflammation, and oxidative stress are known to result in the progressive loss of vulnerable non-regenerative #neurons. (2) Find out more here: https://bit.ly/3SZPklr

MULTI-TARGET DURECTED LIGANDS (MTDLs) IN ALZHEIMER's DISEASE Alzheimer’s disease (AD) is the most common form of dementia affecting specifically older population. AD is an irreversible neurodegenerative CNS disorder associated with complex pathophysiology. Presently, the USFDA has approved only four drugs viz. Donepezil, Rivastigmine, Memantine, and Galantamine for the treatment of AD. These drugs exhibit their neuroprotective effects either by inhibiting cholinesterase enzyme (ChE) or N-methyl-d-aspartate (NMDA) receptor. However, the conventional therapy “one target, one molecule” has failed to provide promising therapeutic effects due to the multifactorial nature of AD. This triggered the development of a novel strategy called Multi-Target Directed Ligand (MTDL) which involved designing one molecule that acts on multiple targets simultaneously. The present review discusses the detailed pathology involved in AD and the various MTDL design strategies. #Alzheimer #MultiTargetDirectedLigand #MTDL #Donepezil #Rivastigmine #Memantine #Galantamine https://lnkd.in/eAQpBtNU

Explore the complex dynamics of biological systems. It's not just an opportunity for interdisciplinary research, but also the potential for an exciting start-up! Simply put, we can have three forms of dynamics: stable equilibrium, rhythms in the form of limit cycles, and complex or chaotic dynamics. Engineered systems often need to be designed to ensure convergence to a stable equilibrium. Biological systems usually have structured oscillatory dynamics as the normal state, for example, heartbeats.    A while ago, Kalyan Chakrabarti, a professionally trained chemist, and I discussed viewing bio-chemical processes through the lens of control and dynamic systems methods. It is great to see this paper in a prestigious journal on bifurcations in processes related to Alzheimer’s disease. When dealing with non-linear systems and bifurcation phenomena in biochemical systems many challenging mathematical questions arise, calling for an interdisciplinary approach involving mathematicians, control engineers, chemists, and biologists.            After adequate progress, a MedTech start-up could offer a wearable device to measure oscillatory dynamics for the early detection of Alzheimer's! Congratulations to the team on the publication – the interface of complex dynamics in biological systems is vast, and I eagerly look forward to seeing the progress. PS: I still need to revert to the Kalyan Chakrabarti research group on our joint work on bio-chemical dynamics!   #ComplexDynamics

Are you interested in complex dynamics of biological systems? In a just published article in npj systems biology and applications (https://lnkd.in/eetiWr6W), we investigate a simple coupled system of amyloid-beta (Ab) aggregation and inflammation relevant in Alzheimer disease (AD) and demonstrate its complex and rich dynamics ranging from overdamped kinetics to sustained oscillations in dependence of various aggregation- and neuroinflammation-related parameters. We suggest that sustained oscillations in inflammatory response to Ab aggregation and its resultant exhaustion of the immune system can lead to a transition to a more progressive phase of amyloid pathology in AD brains. Accordingly, oscillations in aggregation and/or inflammation levels can serve as potential biomarkers in early diagnosis of AD. We also propose that the relative ease of triggering oscillatory dynamics in coupled aggregation-neuroinflammation systems should be taken into consideration in clinical trials related to anti-AD drug development.

Examining the Function of the #BloodBrainBarrier in #TuberousSclerosisComplex New research from the Developmental Synaptopathies Consortium (DSC): https://lnkd.in/gw4fim-U Tuberous sclerosis complex (TSC) is a genetic condition that affects many organs and can cause benign tumors in the skin, kidney, brain, heart, eyes, lungs, and other organs. The most severe symptoms—including seizures, intellectual disability, autism, and behavioral problems—result from complications in the central nervous system. Although these neurological complications are well-understood, less is known about how the genetic mutations that cause TSC might affect different components of the brain, including the blood-brain barrier. In this study, researchers examined the function of the blood-brain barrier in TSC. The team created TSC patient-specific brain tissue models to explore how mutations in the TSC2gene affect the blood-brain barrier. Results show altered function of a blood-brain barrier generated from TSC2 mutant cells, which can improve with treatment of the drug rapamycin or replacement of mutant cells with astrocytes (glial cells in the brain) that do not carry the mutation. Authors note that these findings demonstrate the importance of their methods in ongoing research for TSC and other neurogenetic disorders.