Introduction:Cannabis is increasingly used for pain management, with many patients reporting relief from chronic pain that did not respond to conventional treatments. However, cannabis is also associated with unwanted side effects including psychomimetic effects and the potential of developing a cannabis use disorder. To circumvent the central nervous system effects, we investigated whether a peripherally restricted cannabinoid receptor (CB1) agonist, PrNMI [(4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3yl]ethyl}morpholine] attenuated pain hypersensitivity associated with nerve injury and profiled its' abuse potential. Materials and Methods:Mice with chronic constriction injury (CCI) of the sciatic nerve developed hypersensitivity to mechanical stimulation. Paw withdrawal thresholds were assessed following administration of PrNMI (i.p. 0.3 mg/kg and 0.6 mg/kg) or vehicle in CCI and sham mice. The conditioned place preference model was used to measure drug-reward to 0.6 mg/kg i.p. PrNMI in CCI and sham-injury control animals. We further assessed abuse potential to determine if PrNMI (0.5 mg/kg) would reinstate drug-seeking behavior in mice trained to self-administer intravenous fentanyl (10 μg/kg/infusion). Results:PrNMI administration transiently increased paw withdrawal thresholds in mice with CCI-induced allodynia in a dose-dependent manner. PrNMI conditioning did not produce a conditioned place preference in mice with either CCI or sham injury. Mice who had learned to self-administer fentanyl and went through extinction training did not reinstate drug-seeking behavior when administered PrNMI. Discussion:The systemic CB1 receptor agonist PrNMI demonstrated analgesic benefit in alleviating mechanical allodynia associated with chronic constriction injury of the sciatic nerve without increasing addiction related behaviors associated with the establishment of addiction.

Abstract Substance use disorders (SUDs) are characterized by chronic relapsing episodes of drug seeking and/or drug taking, often despite negative outcomes. Although animal models cannot recapitulate all aspects of SUDs because of the complexities of societal interactions and human-specific processing of rewards and affect, there are many components of SUDs that can be effectively modeled. This chapter reviews the key concepts, advantages, and caveats of using animal models to study initiation, maintenance, and escalation of drug taking, drug taking despite adverse consequences, and drug abstinence and relapse. The chapter discusses the models that have direct translational impact and where there are interpretation limitations. It also reviews the animal models used to interrogate both genetic and environmental factors influencing vulnerability at different stages of SUD. Animal models have made important contributions to the current knowledge of drug-mediated responses and adaptations to brain circuitry that could never have been acquired via human research.

The need for nonaddictive and effective treatments for chronic pain are at an all-time high. Historical precedence, and now clinical evidence, supports the use of cannabis for alleviating chronic pain. A plethora of research on delta-9-tetrahydrocannabinol exists, yet cannabis is comprised of a multitude of constituents, some of which possess analgesic potential, that have not been systematically investigated, including the terpene myrcene. Myrcene attenuates pain hypersensitivity in preclinical models and is one of the most abundant terpenes found in cannabis. Despite these findings, it remains unclear how myrcene elicits these effects on nociceptive systems. The present study uses a male and female mouse model of neuropathic pain as well as in vitro experiments with HEK293T cells to explore these questions. We first demonstrate myrcene (1-200 mg/kg i.p.) dose-dependently increases mechanical nociceptive thresholds, where potency was greater in female compared with male pain mice. Testing canonical tetrad outcomes, mice were tested for hypolocomotion and hypothermia after myrcene administration. Myrcene did not alter locomotion or temperature, but female pain mice showed a conditioned place aversion to myrcene. A cannabinoid receptor 1 (CB1) antagonist inhibited myrcene's anti-allodynia. By contrast, in vitro cell culture experiments using a TRUPATH assay revealed myrcene does not directly activate CB1 receptors nor alter CB1 receptor activity elicited by CB1 agonist (CP 55,940) or endocannabinoids (anandamide or 2-arachidonoylglycerol). Understanding engagement of CB1 receptors in pain modulation and myrcene's mechanism of action warrants further study to understand the diversity of cannabis pharmacology and to further the frontier of pain research.

Recent epidemiological evidence showed that mutations to the HFE-63 allele of this hemochromatosis-associated iron-assimilation protein improve chances of avoiding Alzheimer's disease (AD). This is unexpected since increased brain ferroptosis in gray-matter increases the risk for vascular dementia and AD. However, diffusion tensor imaging from a key Alzheimer's Disease Neuroimaging Initiative biomarker study showed that the hemochromatosis H63D allele protected white matter tracts and improved cognitive performance in individuals when APOE4 accelerates AD. H63D-carrying individuals exhibit elevated serum ferritin levels. We suggest coordinate increased levels of H-ferritin in iron-rich oligodendrocytes in H63D carriers generates sufficient neuroprotection to enhance myelin sheath integrity in white matter axons.

Currently, preclinical research has reported conflicting evidence as to whether chronic pain imparts resilience or vulnerability to opioid drug seeking. Here, we investigated the impact of chronic pain on the intravenous self-administration (IVSA) profile of the short-acting opioid analgesic remifentanil in a mouse model. Using a chronic constriction injury model of chronic neuropathic pain, 7 days after injury, male and female C57Bl/6J mice began remifentanil IVSA. During the acquisition phase, there were no differences in the total number of reinforcers earned but an increase in the number of active nose pokes in pain mice. An increase in the rate of acquisition within sessions was observed in male but not female mice. When work effort increased (fixed ratio 3 and progressive ratio), pain mice unexpectedly showed a reduction in the number of reinforcers earned and their breakpoint. This change in motivational state was specific to the willingness to work for remifentanil, as these changes were not observed with higher effort for a food reward. We hypothesized that chronic pain altered the dopaminergic state of the striatum, which would impact the motivation to work for a reward. We found that pain mice had significantly decreased phasic dopamine release assessed via fast-scan cyclic voltammetry and reduced potassium-evoked extracellular dopamine measured by microdialysis. Future studies will investigate the causal relationship between this hypo-dopaminergic state and decreased behavioral motivation associated with a chronic pain state.

BackgroundAmyloid aggregation of α-Synuclein is a defining feature of several neurodegenerative disorders, including Parkinson's disease (PD), Lewy body dementia (LBD), and Alzheimer's disease (AD). While there have been many attempts to reduce the α-Synuclein burden of neuronal cells through direct targeting of the protein, the conformationally dynamic nature of α-Synuclein make it a particularly difficult target to drug. Given the correlation between α-Synuclein levels and both familial and environmentally induced synucleinopathies, targeting the α-Synuclein mRNA transcript offers an alternative therapeutic avenue.ObjectiveTo develop and evaluate protein-based RNA-binding therapeutics (PROTEIMERs) that selectively bind the 5' untranslated region (UTR) of α-Synuclein mRNA and inhibit its translation to reduce α-Synuclein levels.MethodsWe employed high-throughput phage display to identify novel RNA-binding PROTEIMER candidates targeting the 5'UTR of α-Synuclein mRNA. Binding affinities were assessed via surface plasmon resonance (SPR). Computational structural predictions were used to evaluate PROTEIMER-RNA interactions relative to known regulatory proteins IRP1 and IRP2. RNase domains were fused to the lead PROTEIMERs, and their RNA degradation activity was tested in vitro.ResultsThree PROTEIMERs were identified that bind the α-Synuclein 5'UTR with high affinity. Structural predictions supported specific interactions with the structured RNA region. RNase-fused PROTEIMERs demonstrated targeted RNA degradation and induced decay of α-Synuclein mRNA in vitro, indicating translational suppression capability.ConclusionsOur findings demonstrate the feasibility of using engineered protein therapeutics to target α-Synuclein mRNA via the 5'UTR. These PROTEIMERs represent a promising new strategy for reducing α-Synuclein levels and mitigating neurodegenerative progression in LBD, PD, and AD.

Opioids are a powerful class of medicines due to their ability to alleviate acute pain. However, the use of prescription opioids has led to an epidemic in the United States. Many efforts to combat this are ongoing, including the preparation of misuse deterrent opioid formulations, some of which can be subverted using common household chemicals. Herein, the development of an oxycodone-containing peptide prodrug is reported that contains three covalent misuse deterrent protective layers. This prodrug is resistant to degradation in the presence of acidic and basic pH conditions, common household chemicals, and enzyme supplements. After optimization of the peptide sequence, the lead prodrug is composed of a branched lysine residue coupled to a tert-butyl-protected tyrosine that is not naturally recognized by digestive enzymes. There is a necessary sequence of protecting group removal and then subsequent enzymatic peptide cleavages that trigger cyclization of a self-immolative linker to release the opioid agonist, oxycodone. The prodrug has analgesic properties in vivo in mice only after oral administration and not by intraperitoneal injection, which suggests that this prodrug may have misuse deterrent properties. The specificity for dual-enzyme release and the resulting in vivo studies warrant further examination of this prodrug scaffold for its potential as a misuse deterrent alternative to treat acute pain.

There is extensive interaction between systems involved in pain processing and motivation, where the aberrant functioning of salience circuits likely contributes to chronic pain, as well as increased susceptibility to opioid misuse and opioid use disorder. This study asks to what extent mu opioid receptors (MORs) in dopamine D1 receptor (D1R), D2 receptor (D2R) or adenosine A2a receptor (A2aR) expressing neurons contribute to the expression of pain and opioid antinociception. We ablated MORs in dopamine receptor expressing neurons by breeding D1R, D2R or A2aR-cre with MORloxPmice, which was confirmed by RNAscope multiplex fluorescent in situ hybridization. To determine the role of these MORs in nociception, we assessed the nociceptive responses in the hot plate and formalin tests with and without treatment with oxycodone (3 mg/kg, i.p.). Pain-like behavior in a thermal assay, mechanical thresholds following nerve injury, and the formalin test were not altered by genotype. However, oxycodone-induced antinociception in the formalin test was differentially altered. Opioid antinociception was attenuated in mice that lacked MORs in D1R neurons, but was enhanced when MORs were ablated in either the D2R and A2aR neurons. In contrast, there was no effect of genotype on oxycodone-induced antinociception in the thermal nociceptive test. Together, these data show that MORs in D1R expressing neurons is necessary for opioid-induced antinociception in a model of tonic inflammatory pain, but not acute thermal pain. Whereas, MOR in D2R and A2aR expressing neurons had a tonic inhibitory tone on opioid-mediated antinociception in the formalin test. Perspective: This article presents evidence that mu opioid receptors in dopamine receptor containing neurons differentially modulate opioid antinociception in the formalin test but not threshold evoked phasic pain. The endogenous opioid system in these neuronal populations does not appear to modulate various pain behaviors.

BackgroundThe rising prevalence of Alzheimer's disease (AD) highlights the urgent need for novel therapeutic approaches capable of suppressing further neurodegeneration. Aberrant aggregation of the amyloid-β peptide fragment of the amyloid-β protein precursor (APP) has long been considered to be a central feature of AD pathology. However, directly targeting the amyloid-β peptide is complicated by its conformational flexibility. Instead, reducing APP expression at the translational level represents a promising alternative. The highly structured 5' untranslated region (UTR) of APP mRNA provides a targetable element for selective inhibition using RNA-binding therapeutics.ObjectiveTo develop and evaluate engineered protein-based RNA binders (PROTEIMERs) that selectively target the APP 5'-UTR to inhibit translation.MethodsWe applied high-throughput phage display screening techniques to identify two PROTEIMERs with high affinity for the APP 5'-UTR, confirmed via surface plasmon resonance. Domain engineering enabled the fusion of these binders to an RNase domain to facilitate catalytic degradation of APP mRNA.ResultsPROTEIMERs bound the APP 5'-UTR with nanomolar affinity. Structural modeling of the PROTEIMER-RNA complexes revealed that the engineered mutations within the binding pocket predominantly interact with the 5'-AGA-3' cleft of the APP mRNA. RNase-fused PROTEIMERs mediated sequence-specific APP mRNA cleavage in vitro, demonstrating robust target engagement and degradation. The PROTEIMER ProAPPS3-11 effectively inhibited APP translation in SH-SY5Y cells, reducing protein levels by up to 60% in a dose-dependent manner.ConclusionsThese findings establish the feasibility of PROTEIMERs as novel RNA-targeting biologics with therapeutic potential to reduce APP mRNA and protein levels, mitigating downstream AD-related neurodegeneration.

We aimed to review clinical research on the safety profiles of antidepressant drugs and associations with maternal depression and neonatal outcomes. We focused on neuroendocrine changes during pregnancy and their effects on antidepressant pharmacokinetics. Pregnancy-induced alterations in drug disposition and metabolism impacting mothers and their fetuses are discussed. We considered evidence for the risks of antidepressant use during pregnancy. Teratogenicity associated with ongoing treatment, new prescriptions during pregnancy, or pausing medication while pregnant was examined. The Food and Drug Administration advises caution regarding prenatal exposure to most drugs, including antidepressants, largely owing to a dearth of safety studies caused by the common exclusion of pregnant individuals in clinical trials. We contrasted findings on antidepressant use with the lack of treatment where detrimental effects to mothers and children are well researched. Overall, drug classes such as selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors appear to have limited adverse effects on fetal health and child development. In the face of an increasing prevalence of major mood and anxiety disorders, we assert that individuals should be counseled before and during pregnancy about the risks and benefits of antidepressant treatment given that withholding treatment has possible negative outcomes. Moreover, newer therapeutics, such as ketamine and κ-opioid receptor antagonists, warrant further investigation for use during pregnancy. Significance Statement The safety of antidepressant use during pregnancy remains controversial owing to an incomplete understanding of how drug exposure affects fetal development, brain maturation, and behavior in offspring. This leaves pregnant people especially vulnerable, as pregnancy can be a highly stressful experience for many individuals, with stress being the biggest known risk factor for developing a mood or anxiety disorder. This review focuses on perinatal pharmacotherapy for treating mood and anxiety disorders, highlighting the current knowledge and gaps in our understanding of consequences of treatment.

With rapid expansion of cannabis legalization worldwide, rates of cannabis use and cannabis use disorder (CUD) are increasing; the need for safe and effective medications to treat CUD is urgent. This narrative review evaluates evidence for promising pharmacotherapies to treat CUD from randomized, placebo-controlled trials. Pharmacotherapies for CUD are categorized based on compound targets (e.g., cannabinoid receptor 1 [CB1] agonists such as nabilone, serotonergic compounds such as bupropion, GABAergic compounds such as zolpidem) and outcomes are organized by predetermined withdrawal symptoms, cannabis craving, and cannabis relapse/use. Most promising pharmacotherapies for CUD are drugs that act on the endocannabinoid system and specifically at the CB1 receptor. Priority populations such as females, certain racial/ethnic groups, and age groups experience a different course of CUD progression, symptoms, and drug effects that are important to consider when evaluating outcomes related to CUD. Possible explanations for these disparities are explored, along with the clinical trials that explore these demographics in treating CUD with pharmacotherapies.

A compound has been discovered that increases the potency and duration of action of naloxone, a drug used to reverse the effects of opioid overdoses — possibly opening up another way to save lives. A compound that boosts the effects of a therapy for opioid overdoses.

Brain-Derived Neurotrophic Factor (BDNF) is implicated in extinction learning, which is a primary mechanism of exposure therapy for posttraumatic stress disorder (PTSD). Brief aerobic exercise has been shown to promote BDNF release and augment extinction learning. On the premise that the Val allele of the BDNF Val66Met polymorphism facilitates greater release of BDNF, this study examined the extent to which the Val allele of the BDNF polymorphism predicted treatment response in PTSD patients who underwent exposure therapy combined with aerobic exercise or passive stretching. PTSD patients (N = 85) provided saliva samples in order to extract genomic DNA to identify Val/Val and Met carriers of the BDNF Val66Met genotype, and were assessed for PTSD severity prior to and following a 9-week course of exposure therapy combined with aerobic exercise or stretching. The sample comprised 52 Val/Val carriers and 33 Met carriers. Patients with the BDNF high-expression Val allele display greater reduction of PTSD symptoms at posttreatment than Met carriers. Hierarchical regression analysis indicated that greater PTSD reduction was specifically observed in Val/Val carriers who received exposure therapy in combination with the aerobic exercise. This finding accords with animal and human evidence that the BDNF Val allele promotes greater extinction learning, and that these individuals may benefit more from exercise-augmented extinction. Although preliminary, this result represents a possible avenue for augmented exposure therapy in patients with the BDNF Val allele.

Opioid use disorder (OUD) is associated with a history of early-life adversity (ELA), an association that is particularly strong in women. In a rodent model, we previously found that ELA enhances risk for opioid addiction selectively in females, but the mechanisms for this effect are unclear. Here, we show that ELA robustly alters cFos responses to opioid drugs in females’ nucleus accumbens (NAc) and basolateral amygdala (BLA), but not elsewhere. We further identify delta opioid receptors (DOR), which mature in the first week of life and thus later than kappa or mu opioid receptors, as a potential mediator of ELA's impacts on reward circuit functions. Accordingly, DOR mRNA in NAc was persistently reduced in adult females with ELA history. Moreover, pharmacological stimulation of NAc DORs increased opioid demand in control females (recapitulating the ELA phenotype), while blocking DORs in ELA females conversely reduced high-effort drug consumption, simulating the control rearing phenotype. These findings support a role for NAc DORs in mediating ELA-induced opioid vulnerability. In contrast, BLA neurons expressing DOR protein do not overlap heroin- responsive cells in ELA rats, arguing against a direct relationship of BLA DORs to heroin's addiction-relevant actions in the brain. Together, these results suggest a novel and selective role for NAc DORs in contributing to enduring, ELA-provoked vulnerability to OUD.

Manganese (Mn) is an essential heavy metal in the human body, while excess Mn leads to neurotoxicity, as observed in this study, where 100 µM of Mn was administered to the human neuroblastoma (SH-SY5Y) cell model of dopaminergic neurons in neurodegenerative diseases. We quantitated pathway and gene changes in homeostatic cell-based adaptations to Mn exposure. Utilizing the Gene Expression Omnibus, we accessed the GSE70845 dataset as a microarray of SH-SY5Y cells published by Gandhi et al. (2018) and applied statistical significance cutoffs at p < 0.05. We report 74 pathway and 10 gene changes with statistical significance. ReactomeGSA analyses demonstrated upregulation of histones (5 out of 10 induced genes) and histone deacetylases as a neuroprotective response to remodel/mitigate Mn-induced DNA/chromatin damage. Neurodegenerative-associated pathway changes occurred. NF-κB signaled protective responses via Sirtuin-1 to reduce neuroinflammation. Critically, Mn activated three pathways implicating deficits in purine metabolism. Therefore, we validated that urate, a purine and antioxidant, mitigated Mn-losses of viability in SH-SY5Y cells. We discuss Mn as a hypoxia mimetic and trans-activator of HIF-1α, the central trans-activator of vascular hypoxic mitochondrial dysfunction. Mn induced a 3-fold increase in mRNA levels for antioxidant metallothionein-III, which was induced 100-fold by hypoxia mimetics deferoxamine and zinc.

Over 50 million Americans endure chronic pain where many do not receive adequate treatment and self-medicate to manage their pain by taking substances like opioids and cannabis. Research has shown high comorbidity between chronic pain and substance use disorders (SUD) and these disorders share many common neurobiological underpinnings, including hypodopaminergic transmission. Drugs commonly used for self-medication such as opioids and cannabis relieve emotional, bothersome components of pain as well as negative emotional affect that perpetuates misuse and increases the risk of progressing towards drug abuse. However, the causal effect between chronic pain and the development of SUDs has not been clearly established. In this review, we discuss evidence that affirms the proposition that chronic pain is a risk factor for the development of opioid and cannabis use disorders by outlining the clinical evidence and detailing neurobiological mechanisms that link pain and drug misuse. Central to the link between chronic pain and opioid and cannabis misuse is hypodopaminergic transmission and the modulation of dopamine signaling in the mesolimbic pathway by opioids and cannabis. Moreover, we discuss the role of kappa opioid receptor activation and neuroinflammation in the context of dopamine transmission, their contribution to opioid and cannabis withdrawal, along with potential new treatments.

ImportanceAlthough grief-focused cognitive behavior therapies are the most empirically supported treatment for prolonged grief disorder, many people find this treatment difficult. A viable alternative for treatment is mindfulness-based cognitive therapy.ObjectiveTo examine the relative efficacies of grief-focused cognitive behavior therapy and mindfulness-based cognitive therapy to reduce prolonged grief disorder severity.Design, Setting, and ParticipantsA single-blind, parallel, randomized clinical trial was conducted among adults aged 18 to 70 years with prolonged grief disorder, as defined in the International Classification of Diseases, 11th Revision, and assessed by clinical interview based on the Prolonged Grief−13 (PG-13) scale. Those with severe suicidal risk, presence of psychosis, or substance dependence were excluded. Between November 2012 and November 2022, eligible participants were randomized 1:1 to eleven 90-minute sessions of grief-focused cognitive behavior therapy or mindfulness-based cognitive therapy at a traumatic stress clinic in Sydney, Australia, with follow-up through 6 months.InterventionsBoth groups received once-weekly 90-minute individual sessions for 11 weeks. Grief-focused cognitive behavior therapy comprised 5 sessions of recalling memories of the deceased, plus cognitive restructuring and planning future social and positive activities. Mindfulness-based cognitive therapy comprised mindfulness exercises adapted to tolerate grief-related distress.Main Outcomes and MeasuresThe primary outcome was change in prolonged grief disorder severity measured by the PG-13 scale assessed at baseline, 1 week posttreatment, and 6 months after treatment (primary outcome time point), as well as secondary outcome measures of depression, anxiety, grief-related cognition, and quality of life.ResultsThe trial included 100 participants (mean [SD] age, 47.3 [13.4] years; 87 [87.0%] female), 50 in the grief-focused cognitive behavior therapy condition and 50 in the mindfulness-based cognitive therapy condition. Linear mixed models indicated that at the 6-month assessment, participants in the grief-focused cognitive behavior therapy group showed greater reduction in PG-13 scale score relative to those in the mindfulness-based cognitive therapy group (mean difference, 7.1; 95% CI, 1.6-12.5; P = .01), with a large between-group effect size (0.8; 95% CI, 0.2-1.3). Participants in the grief-focused cognitive behavior therapy group also demonstrated greater reductions in depression as measured on the Beck Depression Inventory than those in the mindfulness-based cognitive therapy group (mean difference, 6.6; 95% CI, 0.5-12.9; P = .04) and grief-related cognition (mean difference, 14.4; 95% CI, 2.8-25.9; P = .02). There were no other significant differences between treatment groups and no reported adverse events.Conclusions and RelevanceIn this study, grief-focused cognitive behavior therapy conferred more benefit for core prolonged grief disorder symptoms and associated problems 6 months after treatment than mindfulness-based cognitive therapy. Although both treatments may be considered for prolonged grief disorder, grief-focused cognitive behavior therapy might be the more effective choice, taking all factors into consideration.Trial Registrationanzctr.org.au Identifier: ACTRN12612000307808

EDITORIAL article Front. Syst. Neurosci., 13 June 2023 Volume 17 - 2023 | https://doi.org/10.3389/fnsys.2023.1212650

Abstract The Center for Disease Control and Prevention estimates that 75% of reported cases of traumatic brain injury (TBI) are mild, where chronic pain and depression are 2 of the most common symptoms. In this study, we used a murine model of repeated mild TBI to characterize the associated pain hypersensitivity and affective-like behavior and to what extent microglial reactivity contributes to these behavioral phenotypes. Male and female C57BL/6J mice underwent sham or repeated mild traumatic brain injury (rmTBI) and were tested for up to 9 weeks postinjury, where an anti-inflammatory/neuroprotective drug (minocycline) was introduced at 5 weeks postinjury in the drinking water. Repeated mild traumatic brain injury mice developed cold nociceptive hypersensitivity and negative affective states, as well as increased locomotor activity and risk-taking behavior. Minocycline reversed negative affect and pain hypersensitivities in male but not female mice. Repeated mild traumatic brain injury also produced an increase in microglial and brain-derived neurotropic factor mRNA transcripts in limbic structures known to be involved in nociception and affect, but many of these changes were sex dependent. Finally, we show that the antiepileptic drug, gabapentin, produced negative reinforcement in male rmTBI mice that was prevented by minocycline treatment, whereas rmTBI female mice showed a place aversion to gabapentin. Collectively, pain hypersensitivity, increased tonic-aversive pain components, and negative affective states were evident in both male and female rmTBI mice, but suppression of microglial reactivity was only sufficient to reverse behavioral changes in male mice. Neuroinflammation in limbic structures seems to be a contributing factor in behavioral changes resulting from rmTBI.

Familial Alzheimer's disease (fAD) mutations in the amyloid-β protein precursor (AβPP) enhance brain AβPP C-Terminal Fragment (CTF) levels to inhibit lysosomal v-ATPase. Consequent disrupted acidification of the endolysosomal pathway may trigger brain iron deficiencies and mitochondrial dysfunction. The iron responsive element (IRE) in the 5'Untranslated-region of AβPP mRNA should be factored into this cycle where reduced bioavailable Fe-II would decrease IRE-dependent AβPP translation and levels of APP-CTFβ in a cycle to adaptively restore iron homeostasis while increases of transferrin-receptors is evident. In healthy younger individuals, Fe-dependent translational modulation of AβPP is part of the neuroprotective function of sAβPPα with its role in iron transport.