Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Авг. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Язык: Английский

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Altered glucose metabolism in Alzheimer's disease: Role of mitochondrial dysfunction and oxidative stress

Free Radical Biology and Medicine, Год журнала: 2022, Номер 193, С. 134 - 157

Опубликована: Окт. 4, 2022

Язык: Английский

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The interaction between ageing and Alzheimer's disease: insights from the hallmarks of ageing

Translational Neurodegeneration, Год журнала: 2024, Номер 13(1)

Опубликована: Янв. 23, 2024

Abstract Ageing is a crucial risk factor for Alzheimer’s disease (AD) and characterised by systemic changes in both intracellular extracellular microenvironments that affect the entire body instead of single organ. Understanding specific mechanisms underlying role ageing development can facilitate treatment ageing-related diseases, such as AD. Signs brain have been observed AD patients animal models. Alleviating pathological caused dramatically ameliorate amyloid beta- tau-induced neuropathological memory impairments, indicating plays pathophysiological process In this review, we summarize impact several age-related factors on propose preventing promising strategy improving cognitive health.

Язык: Английский

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A synergetic turn in cognitive neuroscience of brain diseases

Trends in Cognitive Sciences, Год журнала: 2024, Номер 28(4), С. 319 - 338

Опубликована: Янв. 21, 2024

Язык: Английский

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Roles of Cytokines in Alzheimer’s Disease

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(11), С. 5803 - 5803

Опубликована: Май 26, 2024

The neuroimmune system is a collection of immune cells, cytokines, and the glymphatic that plays pivotal role in pathogenesis progression Alzheimer’s disease (AD). Of particular focus are group signaling molecules facilitate communication among cells contribute to inflammation AD. Extensive research has shown dysregulated secretion certain cytokines (IL-1β, IL-17, IL-12, IL-23, IL-6, TNF-α) promotes neuroinflammation exacerbates neuronal damage However, anti-inflammatory (IL-2, IL-3, IL-33, IL-35) also secreted during AD onset progression, thereby preventing neuroinflammation. This review summarizes involvement pro- pathology discusses their therapeutic potential.

Язык: Английский

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Understanding glucose metabolism and insulin action at the blood–brain barrier: Implications for brain health and neurodegenerative diseases

Acta Physiologica, Год журнала: 2025, Номер 241(2)

Опубликована: Янв. 16, 2025

The blood-brain barrier (BBB) is a highly selective, semipermeable critical for maintaining brain homeostasis. BBB regulates the transport of essential nutrients, hormones, and signaling molecules between bloodstream central nervous system (CNS), while simultaneously protecting from potentially harmful substances pathogens. This selective permeability ensures that nourished shielded toxins. An exception to this are regions, such as hypothalamus circumventricular organs, which irrigated by fenestrated capillaries, allowing rapid direct response various blood components. We overview metabolic functions BBB, with an emphasis on impact altered glucose metabolism insulin in pathogenesis neurodegenerative diseases. Notably, endothelial cells constituting exhibit distinct characteristics, primarily generating ATP through aerobic glycolysis. occurs despite their exposure abundant oxygen bloodstream, typically supports oxidative phosphorylation. effects astrocytes, form glial limitans component show marked sexual dimorphism. nutrient sensing hypothalamus, along signaling, systemic metabolism. Insulin modifies regulating expression tight junction proteins, angiogenesis, vascular remodeling, well modulating flow brain. disruptions particularly evident diseases, Alzheimer's disease Parkinson's disease, where breakdown accelerates cognitive decline. review highlights role normal functionality investigates how these pathways contribute onset progression

Язык: Английский

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DeepDrug as an expert guided and AI driven drug repurposing methodology for selecting the lead combination of drugs for Alzheimer’s disease

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 15, 2025

Язык: Английский

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A predictive coding framework of allostatic–interoceptive overload in frontotemporal dementia

Trends in Neurosciences, Год журнала: 2022, Номер 45(11), С. 838 - 853

Опубликована: Сен. 1, 2022

Allostatic–interoceptive predictive coding frameworks suggest that regulation of the body's internal milieu is required to predict and meet needs generated from environmental demands before they arise.A multilevel organization allostatic–interoceptive measures proposed across cerebral, cardiocerebral, peripheral, psychological levels.Behavioral variant frontotemporal dementia (bvFTD) characterized by disparate autonomic, behavioral, pathophysiological manifestations seem parallel an overload.Under a model, deficits are explained mismatch between top-down bottom-up predictions prediction errors at hierarchies impaired in bvFTD, providing novel framework for characterization, diagnosis, interventions bvFTD patients. Recent explanations using models propose efficient necessary correctly anticipate needs. We review this applied understanding behavioral considering both allostatic overload interoceptive deficits. First, we show how could explain divergent (cognitive impairments, maladjustment, brain atrophy, fronto-insular-temporal network atypicality, aberrant electrophysiological activity, autonomic disbalance). develop set theory-driven based on levels interoception associated with phenomenology related physiopathological mechanisms. This approach may help further understand dysregulations suggesting targeted strengthening clinical neurological psychiatric disorders. In recent years, theories linking allostasis (see Glossary) have gained considerable attention neuroscience [1.Petzschner F.H. et al.Computational body regulation.Trends Neurosci. 2021; 44: 63-76Abstract Full Text PDF PubMed Google Scholar, 2.Nord C.L. Garfinkel S.N. Interoceptive pathways treat mental health conditions.Trends Cogn. Sci. 2022; 26: 499-513Abstract 3.Quigley K.S. al.Functions interoception: energy experience self.Trends 29-38Abstract 4.Kleckner I.R. al.Evidence large-scale system supporting humans.Nat. Hum. Behav. 2017; 1: 0069Crossref Scopus (213) 5.Schulkin J. Sterling P. Allostasis: brain-centered, mode physiological 2019; 42: 740-752Abstract (64) 6.Sterling Homeostasis vs implications function disorders.JAMA Psychiatry. 2014; 71: 1192-1193Crossref (48) Scholar]. Predictive refers assumption actively continuously anticipating updating (exteroception) (interoception) models. One advantage it can be instantiated several biological substrates (Figure 1A ). Allostasis process continuous adjustment organism (e.g., blood pressure, temperature) anticipate, adapt to, changes [7.Guidi al.Allostatic load its impact health: systematic review.Psychother. Psychosom. 2020; 90: 11-27Crossref (147) Scholar] sensing signals [8.Tsakiris M. Critchley H. Interoception beyond homeostasis: affect, cognition health.Philos. Trans. R. Soc. Lond. Ser. B Biol. 2016; 371: 20160002Crossref (0) Together, processes jointly contribute meeting upcoming through model increasing supply fight or flight situation, lowering heart rate when going sleep, reducing flow skin capillaries preserve core temperature, Figure 1B). such models, sensory inputs represented low neural computational hierarchy, while complex interpretations constitute higher levels. Based statistical assumptions, each level predicts activity lower level. The difference anticipation feeling pain getting vaccinated, thus tensing arm muscles) actual input not even needle) generates error, which sent back order correct future relaxing muscles receiving vaccines). [9.Kocagoncu E. abnormal dementia.Brain. 144: 3311-3321Crossref (5) Scholar,10.Birba A. al.Allostatic-interoceptive dementia.Biol. 92: 54-67Abstract (3) other disorders [2.Nord Scholar,11.Barrett L.F. al.An active inference theory depression.Philos. 20160011Crossref article, evidence extend these (bvFTD), most common presentation lobar degeneration. It early personality, social behavior, self-regulation, executive functions, motivation, emotional [12.Piguet O. al.Behavioural-variant dementia: staging, management.Lancet Neurol. 2011; 10: 162-172Abstract (374) 13.Piguet Kumfor F. Frontotemporal dementias: main syndromes underlying changes.Curr. Opin. 33: 215-221Crossref (6) 14.Possin K.L. al.Dissociable functions Alzheimer dementias.Neurology. 2013; 80: 2180-2185Crossref (76) presents pattern progressive neurodegeneration involving fronto-temporo-insular regions [15.Kril J.J. Halliday G.M. Clinicopathological staging severity: correlation regional atrophy.Dement. Geriatr. Disord. 2004; 17: 311-315Crossref These neurocognitive consequence malfunctions dynamics [10.Birba Of note, alterations been observed neurodegenerative conditions variants FTD. For instance, convergent supports Alzheimer's disease, as Parkinson's disease multiple sclerosis (Box 1). Despite transnosological alterations, would argue seems fairly specific bvFTD: bvFTD's multimodal compromise autonomic-interoceptive pathways, different levels, responses distinctively fit account.Box 1Transnosological bvFTDBoth dimensional compromised many conditions.Allostatic closely pathophysiology, specifically regarding bidirectional association insulin signaling [121.De Felice F.G. al.Impaired signalling disease.Nat. Rev. 23: 215-230Crossref Lifestyle factors during life load, lead become chronically harmful. Such state trigger brain, including oxidative stress chronic inflammation, leading resistance predisposing alternative approaches traditional amyloid cascade hypothesis consider crucial factor development progression [122.Luczkowski "No screams cries will convince us white black black", ode defenders disease.Coord. Chem. 327-328: 35-42Crossref Scholar].bvFTD appears only (behavioral, peripherical, HEP, neurofunctional) impairments dimensions. dysregulations, however, also present [123.Bonaz B. al.Diseases, disorders, comorbidities interoception.Trends 39-51Abstract Although without conflicting results, individuals tend performance tasks [28.Abrevaya S. al.At dimensionality: cross-nosological cardiac deficits.Psychosom. Med. 82: 850-861Crossref (8) along modulations addition awareness learning [124.Garcia-Cordero I. al.Metacognition emotion recognition diseases.Cortex. 137: 93-107Crossref Moreover, [125.Ricciardi L. al.Know thyself: exploring sensitivity disease.J. 364: 110-115Abstract Scholar,126.Christopher al.Uncovering role insula non-motor symptoms disease.Brain. 2143-2154Crossref Scholar], distinguish among postural instability/gait difficulty tremor dominant [127.Santangelo G. al.Interoceptive processing deficit: marker subtyping disease.Parkinsonism Relat. 2018; 53: 64-69Abstract Similarly, [29.Salamone P.C. al.Altered signatures sclerosis.Hum. Brain Mapp. 39: 4743-4754Crossref (11) linked cardinal fatigue [128.Gonzalez Campo C. al.Fatigue abnormalities.Mult. Scler. 1845-1853Crossref (19) Thus, spreading over bordering hubs diseases deficits.Despite presence diseases, combined bvFTD. affection autonomic–interoceptive uniquely fits account. antecedents, sui generis neurodegeneration-triggered influence imprecise precision, manifestations. Both conditions. Allostatic first available imbalance system, Then, subsumed into multidimensional integrating markers assessments inference. Under framework, cognitive with: (i) structural connectivity critical hubs, (ii) altered (iii) biomarker within account, offer accounts allostasis, sources information about [16.McEwen B.S. al.Mechanisms brain.Nat. 2015; 18: 1353-1363Crossref (728) Importantly, open new possibilities assessing brain–body–environment synergetic interactions [17.Ibanez mind's golden cage wild.Trends https://doi.org/10.1016/j.tics.2022.07.008Abstract integrated profile 2). Neuroimaging techniques identified domain-general (AIN) integrates visceromotor 2A). connects wide range domains memory, function, processing, control, [4.Kleckner AIN involves network, 'neural backbone' brain's coordinated activity. composed salience (bilateral ventral dorsal anterior insula, cingulate cortex, striatum, thalamus, central nucleus amygdala, hypothalamus, brainstem) default angular gyrus, precuneus, hippocampus, medial prefrontal cortices). neuroanatomically defined Scholar,18.McEwen Allostasis, aging nervous system: excitatory amino acids excitotoxicity.Neurochem. Res. 2000; 25: 1219-1231Crossref maintain balance information. Specifically, limbic cortices project hypothalamus brainstem nuclei monitor neuroendocrine, immune systems. interpreted anatomical paths cortices. Also, under interpretation, send carry outcomes primary parallel, projected vagus nerve cortices, where contrasted, resulting error As such, regulates cardiocerebral peripheral together environment. example, adults history infant regulatory problems selectively networks (AIN subnetworks) assessed resting-state functional magnetic resonance imaging (rsfMRI) [19.Bäuml J.G. al.The mediates adult avoidant personality traits.Biol. Psychiatry Neuroimaging. 4: 333-342Abstract organs gut structure interactions, principles hierarchical discussed more detail later sections. understood cost sustaining [3.Quigley saturation due cumulative burden events referred overload. state, exposed repeated evoking neuroendocrine Behavioral examples include over-reacting under-reacting stressors. various description 2B). include: cerebral measurements metrics Scholar]; estimations [20.Coll M.P. al.Systematic meta-analysis relationship heartbeat-evoked potential interoception.Neurosci. Biobehav. 122: 190-200Crossref (30) biomarkers [21.Shiels P.G. al.Circulating ageing load: slow train coming.Pract. Lab. 7: 49-54Crossref Scholar,22.Wright K.D. al.Beyond focused African American older adults.Res. Gerontol. Nurs. 14: 222-224Crossref (1) (iv) testing relations subjective objective arousal psychosocial evaluating dysregulated [23.Piolanti al.Use index: sensitive tool research practice.Psychother. 85: 337-345Crossref (34) Scholar,24.Fava G.A. al.Current psychosomatic 86: 13-30Crossref (144) At 2B), anatomical/structural quantify degree interaction nodes form AIN. integrity measured methods voxel-based morphometry, diffusion tensor imaging, rsfMRI 2B) partially indexed heart-evoked (HEP), brain–body characteristic activated visceral regulated ability feel electroencephalography source localization studies [25.Pollatos al.Brain structures involved cardioafferent signal processing: dipole study.Hum. 2005; 54-64Crossref (170) Scholar,26.Al al.Heart-brain shape somatosensory perception evoked potentials.Proc. Natl. Acad. U. 117: 10575-10584Crossref associate HEP processes. heartbeat detection tasks, participants must press key time [27.García-Cordero al.Feeling, being aware inner states: dimensions stroke.Philos. 20160006Crossref 28.Abrevaya 29.Salamone 30.Salamone al.Dynamic after transplant.Brain Commun. 2: fcaa095Crossref 31.Canales-Johnson al.Auditory feedback differentially modulates tapping your heartbeat.Cereb. Cortex. 4490-4503Crossref (82) 32.Yoris world

Язык: Английский

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Patchouli alcohol attenuates the cognitive deficits in a transgenic mouse model of Alzheimer’s disease via modulating neuropathology and gut microbiota through suppressing C/EBPβ/AEP pathway

Journal of Neuroinflammation, Год журнала: 2023, Номер 20(1)

Опубликована: Янв. 30, 2023

Abstract Background Alzheimer’s disease (AD) is a chronic neurodegenerative characterized by progressive cognitive dysfunctions and behavioral impairments. Patchouli alcohol (PA), isolated from Pogostemonis Herba , exhibits multiple pharmacological properties, including neuroprotective effects. This study aimed to investigate the therapeutic effects of PA against AD using TgCRND8 transgenic mouse model, explore underlying mechanisms targeting CCAAT/enhancer-binding protein β/asparagine endopeptidase (C/EBPβ/AEP) signaling pathway. Methods After genotyping confirm transgenicity, drug treatments were administered intragastrically once daily 3-month-old mice for 4 consecutive months. Several tests applied assess different aspects neurological functions. Then brain colon tissues harvested in-depth mechanistic studies. To further verify whether exerts anti-AD via modulating C/EBPβ/AEP pathway in mice, adeno-associated virus (AAV) vectors encoding CEBP/β bilaterally injected into hippocampal CA1 region overexpress C/EBPβ. Additionally, fecal microbiota transplantation (FMT) experiment was performed potential role gut on PA. Results Our results showed that treatment significantly improved activities living (ADL), ameliorated anxiety-related deficits impairments mice. modulated amyloid precursor (APP) processing. also markedly reduced levels beta-amyloid (Aβ) 40 Aβ 42 suppressed plaque burdens, inhibited tau hyperphosphorylation at several sites relieved neuroinflammation brains Moreover, restored dysbiosis activation Interestingly, strikingly alleviated AD-like pathologies induced overexpression C/EBPβ FMT PA-treated germ-free Conclusion All these findings amply demonstrated could ameliorate suppressing plaques deposition, protein, through inhibiting pathway, suggesting promising naturally occurring chemical worthy development pharmaceutical AD.

Язык: Английский

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Addressing the gaps between socioeconomic disparities and biological models of dementia

Brain, Год журнала: 2023, Номер 146(9), С. 3561 - 3564

Опубликована: Июль 11, 2023

How do socioeconomic disparities shape brain health and disease? Ibáñez et al. discuss the need for further research into how wealth status affect biological models of dementia, highlighting ripple effects inequalities importance globally inclusive research.

Язык: Английский

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