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Redox Biology Dec 2023Oxygen metabolism abnormality plays a crucial role in the pathogenesis of Alzheimer's disease (AD) via several mechanisms, including hypoxia, oxidative stress, and... (Review)
Review
Oxygen metabolism abnormality plays a crucial role in the pathogenesis of Alzheimer's disease (AD) via several mechanisms, including hypoxia, oxidative stress, and mitochondrial dysfunction. Hypoxia condition usually results from living in a high-altitude habitat, cardiovascular and cerebrovascular diseases, and chronic obstructive sleep apnea. Chronic hypoxia has been identified as a significant risk factor for AD, showing an aggravation of various pathological components of AD, such as amyloid β-protein (Aβ) metabolism, tau phosphorylation, mitochondrial dysfunction, and neuroinflammation. It is known that hypoxia and excessive hyperoxia can both result in oxidative stress and mitochondrial dysfunction. Oxidative stress and mitochondrial dysfunction can increase Aβ and tau phosphorylation, and Aβ and tau proteins can lead to redox imbalance, thus forming a vicious cycle and exacerbating AD pathology. Hyperbaric oxygen therapy (HBOT) is a non-invasive intervention known for its capacity to significantly enhance cerebral oxygenation levels, which can significantly attenuate Aβ aggregation, tau phosphorylation, and neuroinflammation. However, further investigation is imperative to determine the optimal oxygen pressure, duration of exposure, and frequency of HBOT sessions. In this review, we explore the prospects of oxygen metabolism in AD, with the aim of enhancing our understanding of the underlying molecular mechanisms in AD. Current research aimed at attenuating abnormalities in oxygen metabolism holds promise for providing novel therapeutic approaches for AD.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Oxygen; Neuroinflammatory Diseases; tau Proteins; Hypoxia
PubMed: 37956598
DOI: 10.1016/j.redox.2023.102955 -
Biomedicine & Pharmacotherapy =... Sep 2023Alzheimer's disease (AD) is the most common neurodegenerative disease, resulting in the loss of cognitive ability and memory. However, there is no specific treatment to... (Review)
Review
Alzheimer's disease (AD) is the most common neurodegenerative disease, resulting in the loss of cognitive ability and memory. However, there is no specific treatment to mechanistically inhibit the progression of Alzheimer's disease, and most drugs only provide symptom relief and do not fundamentally reverse AD. Current studies show that triggering receptor expressed on myeloid cells 2 (TREM2) is predominantly expressed in microglia of the central nervous system (CNS) and is involved in microglia proliferation, survival, migration and phagocytosis. The current academic view suggests that TREM2 and its ligands have CNS protective effects in AD. Specifically, TREM2 acts by regulating the function of microglia and promoting the clearance of neuronal toxic substances and abnormal proteins by microglia. In addition, TREM2 is also involved in regulating inflammatory response and cell signaling pathways, affecting the immune response and regulatory role of microglia. Although the relationship between TREM2 and Alzheimer's disease has been extensively studied, its specific mechanism of action is not fully understood. The purpose of this review is to provide a comprehensive analysis of the research of TREM2, including its regulation of the inflammatory response, lipid metabolism and phagocytosis in microglia of CNS in AD, and to explore the potential application prospects as well as limitations of targeting TREM2 for the treatment of AD.
Topics: Humans; Alzheimer Disease; Microglia; Neurodegenerative Diseases; Central Nervous System; Phagocytosis; Membrane Glycoproteins; Receptors, Immunologic
PubMed: 37517293
DOI: 10.1016/j.biopha.2023.115218 -
Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer's disease.Nature Medicine Aug 2023Alzheimer's disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes-aggregation of the amyloid-β (Aβ) peptide...
Alzheimer's disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes-aggregation of the amyloid-β (Aβ) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)-are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of Aβ plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with Aβ plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than Aβ and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with Aβ and tau.
Topics: Humans; Alzheimer Disease; Biomarkers; Proteomics; Male; Female; Adult; Middle Aged; Mutation; Age of Onset
PubMed: 37550416
DOI: 10.1038/s41591-023-02476-4 -
Advances in Clinical and Experimental... Oct 2023Recently, the U.S. Food and Drug Administration (FDA) approved 2 anti-amyloid monoclonal antibodies, aducanumab (June 7, 2021) and lecanemab (July 6, 2023), for the...
Recently, the U.S. Food and Drug Administration (FDA) approved 2 anti-amyloid monoclonal antibodies, aducanumab (June 7, 2021) and lecanemab (July 6, 2023), for the treatment of Alzheimer's disease (AD) patients, and will most likely also approve a 3rd one, donanemab, soon. While these antibodies have been shown to significantly reduce amyloid in the brain, there is little, if any, evidence that they provide clinically meaningful benefit for AD patients by slowing cognitive decline. I have said it before, and I say it again: the reported benefits of anti-amyloid antibodies observed in clinical trials are erroneous and based on misinterpretation of data and a trivial miscalculation. For example, Sims et al. (2023) reported in a phase III clinical trial that donanemab treatment of early symptomatic AD patients with amyloid and tau pathology provided 35% and 36% slowing of clinical progression and cognitive decline, respectively, as measured using the Integrated Alzheimer's Disease Rating Scale (iADRS) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) psychometric tests. Here, in this editorial, I show that 2.5% and 9.6% would be better estimates for less cognitive impairment with donanemab treatment.
Topics: United States; Humans; Alzheimer Disease; Antibodies, Monoclonal
PubMed: 37831471
DOI: 10.17219/acem/172673 -
Nature Communications Oct 2023Plasma amyloid-β (Aβ)42, phosphorylated tau (p-tau)181, and neurofilament light chain (NfL) are promising biomarkers of Alzheimer's disease (AD). However, whether...
Plasma amyloid-β (Aβ)42, phosphorylated tau (p-tau)181, and neurofilament light chain (NfL) are promising biomarkers of Alzheimer's disease (AD). However, whether these biomarkers can predict AD in Chinese populations is yet to be fully explored. We therefore tested the performance of these plasma biomarkers in 126 participants with preclinical AD and 123 controls with 8-10 years of follow-up from the China Cognition and Aging Study. Plasma Aβ42, p-tau181, and NfL were significantly correlated with cerebrospinal fluid counterparts and significantly altered in participants with preclinical AD. Combining plasma Aβ42, p-tau181, and NfL successfully discriminated preclinical AD from controls. These findings were validated in a replication cohort including 51 familial AD mutation carriers and 52 non-carriers from the Chinese Familial Alzheimer's Disease Network. Here we show that plasma Aβ42, p-tau181, and NfL may be useful for predicting AD 8 years before clinical onset in Chinese populations.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; East Asian People; tau Proteins
PubMed: 37875471
DOI: 10.1038/s41467-023-42596-6 -
Cellular and Molecular Neurobiology Oct 2023The Apolipoprotein E ε4 (ApoE ε4) allele, encoding ApoE4, is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). Emerging epidemiological... (Review)
Review
The Apolipoprotein E ε4 (ApoE ε4) allele, encoding ApoE4, is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). Emerging epidemiological evidence indicated that ApoE4 contributes to AD through influencing β-amyloid (Aβ) deposition and clearance. However, the molecular mechanisms of ApoE4 involved in AD pathogenesis remains unclear. Here, we introduced the structure and functions of ApoE isoforms, and then we reviewed the potential mechanisms of ApoE4 in the AD pathogenesis, including the effect of ApoE4 on Aβ pathology, and tau phosphorylation, oxidative stress; synaptic function, cholesterol transport, and mitochondrial dysfunction; sleep disturbances and cerebrovascular integrity in the AD brains. Furthermore, we discussed the available strategies for AD treatments that target to ApoE4. In general, this review overviews the potential roles of ApoE4 in the AD development and suggests some therapeutic approaches for AD. ApoE4 is genetic risk of AD. ApoE4 is involved in the AD pathogenesis. Aβ deposition, NFT, oxidative stress, abnormal cholesterol, mitochondrial dysfunction and neuroinflammation could be observed in the brains with ApoE4. Targeting the interaction of ApoE4 with the AD pathology is available strategy for AD treatments.
Topics: Humans; Alzheimer Disease; Apolipoprotein E4; Amyloid beta-Peptides; Apolipoproteins E; Brain
PubMed: 37227619
DOI: 10.1007/s10571-023-01365-1 -
Alzheimer's Research & Therapy Oct 2023Development of in vivo biomarkers has shifted the diagnosis of Alzheimer's disease (AD) from the later dementia stages of disease towards the earlier stages and has... (Review)
Review
BACKGROUND
Development of in vivo biomarkers has shifted the diagnosis of Alzheimer's disease (AD) from the later dementia stages of disease towards the earlier stages and has introduced the potential for pre-symptomatic diagnosis. The International Working Group recommends that AD diagnosis is restricted in the clinical setting to people with specific AD phenotypes and supportive biomarker findings.
MAIN BODY
In this review, we discuss the phenotypic presentation and use of biomarkers for the early diagnosis of typical and atypical AD and describe how this can support clinical decision making, benefit patient communication, and improve the patient journey. Early diagnosis is essential to optimize the benefits of available and emerging treatments. As atypical presentations of AD often mimic other dementias, differential diagnosis can be challenging and can be facilitated using AD biomarkers. However, AD biomarkers alone are not sufficient to confidently diagnose AD or predict disease progression and should be supplementary to clinical assessment to help inform the diagnosis of AD.
CONCLUSIONS
Use of AD biomarkers with incorporation of atypical AD phenotypes into diagnostic criteria will allow earlier diagnosis of patients with atypical clinical presentations that otherwise would have been misdiagnosed and treated inappropriately. Early diagnosis is essential to guide informed discussion, appropriate care and support, and individualized treatment. It is hoped that disease-modifying treatments will impact the underlying AD pathology; thus, determining the patient's AD phenotype will be a critical factor in guiding the therapeutic approach and the assessment of the effects of interventions.
Topics: Humans; Alzheimer Disease; Diagnosis, Differential; Biomarkers; Recognition, Psychology; Disease Progression
PubMed: 37833762
DOI: 10.1186/s13195-023-01314-6 -
International Journal of Molecular... Sep 2023Over the past 30 years, the majority of (pre)clinical efforts to find an effective therapy for Alzheimer's disease (AD) focused on clearing the β-amyloid peptide (Aβ)... (Review)
Review
Over the past 30 years, the majority of (pre)clinical efforts to find an effective therapy for Alzheimer's disease (AD) focused on clearing the β-amyloid peptide (Aβ) from the brain since, according to the amyloid cascade hypothesis, the peptide was (and it is still considered by many) the pathogenic determinant of this neurodegenerative disorder. However, as reviewed in this article, results from the numerous clinical trials that have tested anti-Aβ therapies to date indicate that this peptide plays a minor role in the pathogenesis of AD. Indeed, even Aducanumab and Lecanemab, the two antibodies recently approved by the FDA for AD therapy, as well as Donanemab showed limited efficacy on cognitive parameters in phase III clinical trials, despite their capability of markedly lowering Aβ brain load. Furthermore, preclinical evidence demonstrates that Aβ possesses several physiological functions, including memory formation, suggesting that AD may in part be due to a loss of function of this peptide. Finally, it is generally accepted that AD could be the result of many molecular dysfunctions, and therefore, if we keep chasing only Aβ, it means that we cannot see the forest for the trees.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Amyloid; Antibodies, Monoclonal, Humanized; Brain
PubMed: 37833948
DOI: 10.3390/ijms241914499 -
Neuroscience and Biobehavioral Reviews Jul 2023Behavioural inflexibility is a symptom of neuropsychiatric and neurodegenerative disorders such as Obsessive-Compulsive Disorder, Autism Spectrum Disorder and... (Review)
Review
Behavioural inflexibility is a symptom of neuropsychiatric and neurodegenerative disorders such as Obsessive-Compulsive Disorder, Autism Spectrum Disorder and Alzheimer's Disease, encompassing the maintenance of a behaviour even when no longer appropriate. Recent evidence suggests that insulin signalling has roles apart from its regulation of peripheral metabolism and mediates behaviourally-relevant central nervous system (CNS) functions including behavioural flexibility. Indeed, insulin resistance is reported to generate anxious, perseverative phenotypes in animal models, with the Type 2 diabetes medication metformin proving to be beneficial for disorders including Alzheimer's Disease. Structural and functional neuroimaging studies of Type 2 diabetes patients have highlighted aberrant connectivity in regions governing salience detection, attention, inhibition and memory. As currently available therapeutic strategies feature high rates of resistance, there is an urgent need to better understand the complex aetiology of behaviour and develop improved therapeutics. In this review, we explore the circuitry underlying behavioural flexibility, changes in Type 2 diabetes, the role of insulin in CNS outcomes and mechanisms of insulin involvement across disorders of behavioural inflexibility.
Topics: Animals; Alzheimer Disease; Insulin; Autism Spectrum Disorder; Diabetes Mellitus, Type 2; Obsessive-Compulsive Disorder
PubMed: 37059405
DOI: 10.1016/j.neubiorev.2023.105169 -
Redox Biology Oct 2023Microglia activation drives the pro-inflammatory activity in the early stages of Alzheimer's disease (AD). However, the mechanistic basis is elusive, and the hypothesis...
Microglia activation drives the pro-inflammatory activity in the early stages of Alzheimer's disease (AD). However, the mechanistic basis is elusive, and the hypothesis of targeting microglia to prevent AD onset is little explored. Here, we demonstrated that upon LPS exposure, microglia shift towards an energetic phenotype characterised by high glycolysis and high mitochondrial respiration with dysfunction. Although the activity of electron transport chain (ETC) complexes is boosted by LPS, this is mostly devoted to the generation of reactive oxygen species. We showed that by inhibiting succinate dehydrogenase (SDH) with dimethyl malonate (DMM), it is possible to modulate the LPS-induced metabolic rewiring, facilitating an anti-inflammatory phenotype. DMM improves mitochondrial function in a direct way and by reducing LPS-induced mitochondrial biogenesis. Moreover, the block of SDH with DMM inhibits the recruitment of hypoxia inducible-factor 1 α (HIF-1α), which mediates the induction of glycolysis and cytokine expression. Similar bioenergetic alterations were observed in the microglia isolated from AD mice (3xTg-AD), which present high levels of circulating LPS and brain toll-like receptor4 (TLR4). Moreover, this well-established model of AD was used to show a potential effect of SDH inhibition in vivo as DMM administration abrogated brain inflammation and modulated the microglia metabolic alterations of 3xTg-AD mice. The RNA-sequencing analysis from a public dataset confirmed the consistent transcription of genes encoding for ETC subunits in the microglia of AD mice (5xFAD). In conclusion, TLR4 activation promotes metabolic changes and the pro-inflammatory activity in microglia, and SDH might represent a promising therapeutic target to prevent AD development.
Topics: Mice; Animals; Alzheimer Disease; Microglia; Mice, Transgenic; Lipopolysaccharides; Toll-Like Receptor 4; Inflammation
PubMed: 37586250
DOI: 10.1016/j.redox.2023.102846