Towards that end, results were presented recently [144] from a 24-week 161 patient double-blind, placebo controlled clinical trial of a p38 inhibitor neflamapimod in early-stage AD (https://clinicaltrials.gov/ct2/show/”type”:”clinical-trial”,”attrs”:”text”:”NCT03402659″,”term_id”:”NCT03402659″NCT03402659). kinase inhibitors provide the opportunity for significant therapeutic advances in TEF2 neurogenerative disease through normalizing dysregulated Rab5 activity. In this review, we provide a brief summary of the role of Rab5 in the cell and its association with neurodegenerative disease pathogenesis. We then discuss the connection between Rab5 and p38 and summarize the evidence that through modulating Rab5 activity there are therapeutic opportunities in neurodegenerative diseases for p38 kinase inhibitors. have exhibited that Rab5 is required for synaptic endosomal integrity, synaptic vesicle exo-/endocytosis rates, and neurotransmitter probability [54]. Furthermore, an essential function is usually that Rab5-dependent endosomal sorting may regulate the uniformity of synaptic vesicle size [55]. The neuron may be particularly sensitive to dysregulation of Rab5 activity for at least two main reasons: (1) Endocytosis and subsequent recycling (or not) regulate the Bekanamycin concentration of neurotransmitter receptor density around the cell surface, determining signal strength [53,56,57]. For Bekanamycin example, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) endocytosis in hippocampal neurons leads to long-term depressive disorder (LTD), and Rab5 is essential in this process [56,58,59]; and (2) neurotrophin signaling from synapses is dependent on endocytosis, retrograde transport of endosomes along axons, and endosomal signaling [1,48,52,60]. 3.3. Rab5 Therapeutic Targeting Strategies The activity of Rab5 is usually coordinately regulated and, therefore, can be therapeutically targeted at several levels through modulation of Rab5 regulatory proteins. Firstly, Rab5 is usually shuttled between membranes by the general Rab regulator GDP dissociation inhibitor (GDI) [61]. This serves to release Rab5 that is bound to GDP, Rab5(GDP), from membranes to maintain Rab5 in the cytoplasm, and to recycle it back to donor membranes [61]. Thus, factors that increase formation of the Rab5-GDI complex also increase delivery of Rab5 to the plasma membrane where it can act [61]. Secondly, at the membrane, the activity of Rab5 is usually regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) that determine the proportion of Rab5 bound to either GDP (Rab5(GDP); inactive state) or GTP (Rab5(GTP); active state) [62]. Thirdly, Rab5 activity is usually modulated by other factors that impact the effectors; for example, the phosphorylation of, and activity of, PI3K or EEA1 [63,64,65,66]. Additionally, the druggability of membrane-bound Rab5 itself, the selective inhibition of Rab5 GTPase activity, or blocking membrane recruitment through inhibition of Rab5 prenylation, or targeting Rab5-associated signaling pathways can be explored [67,68,69]. 4. Role of Dysregulated Rab5 in the Pathogenesis of Neurodegenerative Disease Dysregulated Rab5 activity has been defined as a major pathogenic driver in AD [1,48,70]. Moreover, a pathogenic role of aberrant Bekanamycin Rab5 is usually emerging in many of the same other neurodegenerative diseases that are being targeted by p38 inhibitor programs, including PD, DLB, ALS, and HD [71,72,73]. Rab5 is usually a member of a large family of Rab proteins involved with neuronal function [53, 71] and a number of other Rab proteins have been connected to neurodegenerative disease. However, as will be discussed in Section 5, Rab5 activity has been robustly connected to p38 MAPK signaling, while no such connection has been established for the other Rab proteins. Therefore, this review is focused on Rab5, and the reader is referred to a number of other excellent recent reviews around the broader family of Rab proteins and their relation to the pathogenesis of neurodegenerative disease [71,72,73]. 4.1. Dysregulated Rab5 as Therapeutic Target in AD Neuronal endocytic pathway activation is usually a specific and very early response in AD that precedes amyloid-beta (A) deposition in sporadic AD, hence, the role of dysregulated Rab5 in AD has been extensively studied and reviewed elsewhere [1,48,70,71]. It will be discussed briefly here. In a large series of experiments during more than two decades, Nixon and colleagues have documented specific impairments of the endosomal-lysosomal system at the earliest stage of AD and linked the genetic drivers that cause AD directly to functions within endocytic and autophagic pathways of the lysosomal system. They exhibited that abnormal Rab5-positive endosome enlargement is the earliest pathologic event in sporadic AD patients [74,75]. They also showed that abnormal Rab5-positive endosome enlargement is the earliest pathologic event in Down syndrome (DS) patients [74,75]. DS patients are.