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EBioMedicine Dec 2023The pattern of olfactory identification change in the early phases of dementing disorders is unclear. We aimed to assess olfactory identification trajectories preceding...
BACKGROUND
The pattern of olfactory identification change in the early phases of dementing disorders is unclear. We aimed to assess olfactory identification trajectories preceding incident mild cognitive impairment (MCI) and dementia and explore the role of brain pathologies in these trajectories.
METHODS
Within the Rush Memory and Aging Project, 1318 dementia-free older adults were followed annually for up to 11 years. Olfactory identification was assessed using the Brief Smell Identification Test annually. Of 900 cognitively intact participants, incident MCI and dementia were diagnosed following standard criteria. Over follow-up, 518 participants died and underwent brain autopsies for neuropathological assessment. Data were analyzed using mixed-effect models with backward timescales.
FINDINGS
Compared to participants who remained cognitively intact, olfactory identification declined faster among those who developed MCI (β -0.09 [95% CI -0.13, -0.05]), leading to a significantly lower olfactory identification starting from five years preceding MCI diagnosis (mean difference at year -5: -0.39 [-0.71, -0.07]). Among participants with incident MCI, olfactory identification declined faster in those who developed dementia compared to those who did not (β -0.19 [-0.36, -0.01]), leading to a significantly lower olfactory identification starting from three years preceding dementia diagnosis (mean difference at year -3: -0.95 [-1.67, -0.23]). A faster decline in olfactory identification was associated with higher burdens of global Alzheimer's disease pathology, neurofibrillary tangles, and amyloid beta load.
INTERPRETATION
Olfactory identification declined faster preceding dementia disorders and Alzheimer's pathology may underlie these faster declines.
FUNDING
This study was funded by the National Institutes of Health (R01AG17917) and Swedish Research Council (2021-01647).
Topics: United States; Humans; Aged; Smell; Longitudinal Studies; Amyloid beta-Peptides; Alzheimer Disease; Cognitive Dysfunction
PubMed: 38251465
DOI: 10.1016/j.ebiom.2023.104862 -
CNS Drugs Aug 2023Alzheimer's disease (AD) is the leading cause of dementia worldwide. Numerous biomarker studies have clearly demonstrated that AD has a long asymptomatic phase, with the... (Review)
Review
Alzheimer's disease (AD) is the leading cause of dementia worldwide. Numerous biomarker studies have clearly demonstrated that AD has a long asymptomatic phase, with the development of pathology occurring at least 2 decades prior to the development of any symptoms. These pathological changes include a stepwise development of amyloid-β (Aβ) plaques, followed by tau neurofibrillary tangles and subsequently extensive neurodegeneration in the brain. In this review, we discuss the first class of drugs intended to be disease modifying to be approved by the US Food and Drug Administration (FDA) for AD-anti-Aβ monoclonal antibodies-and the scientific rationale with which they were developed.
Topics: Humans; Alzheimer Disease; tau Proteins; Antibodies, Monoclonal; Amyloid beta-Peptides; Neurofibrillary Tangles; Amyloid
PubMed: 37470978
DOI: 10.1007/s40263-023-01021-8 -
A Review of the Current Status of Disease-Modifying Therapies and Prevention of Alzheimer's Disease.Medical Science Monitor : International... May 2024Alzheimer's disease is the most common form of dementia and includes cognitive, personality, and behavioral changes. The 2024 report from the Alzheimer's Association... (Review)
Review
Alzheimer's disease is the most common form of dementia and includes cognitive, personality, and behavioral changes. The 2024 report from the Alzheimer's Association estimated that 6.9 million adults >65 years in the US are currently living with Alzheimer's disease. Modeling studies predict that this number will double by 2050, and associated healthcare costs will reach $1 trillion. In June 2021, regulatory approval of aducanumab, a humanized recombinant monoclonal antibody to amyloid ß, initially raised expectations for improved disease-modifying therapy. However, in February 2024, production of aducanumab and a post-marketing clinical trial ceased in the US due to the costs and limitations of aducanumab therapy. In March 2024, biobank data identified significant modifiable risk factors for Alzheimer's disease, including diabetes mellitus, exposure to nitrogen dioxide (a proxy for air pollution), and the frequency of alcohol intake. Therefore, modification of identifiable risk factors, combined with testing for disease-susceptibility genes, could be the most effective approach to reduce the incidence. This article aims to review the current status of disease-modifying therapies and prevention of Alzheimer's disease.
Topics: Alzheimer Disease; Humans; Risk Factors; Antibodies, Monoclonal, Humanized; Amyloid beta-Peptides
PubMed: 38736218
DOI: 10.12659/MSM.945091 -
Acta Neuropathologica May 2024Aging is associated with cell senescence and is the major risk factor for AD. We characterized premature cell senescence in postmortem brains from non-diseased controls...
Aging is associated with cell senescence and is the major risk factor for AD. We characterized premature cell senescence in postmortem brains from non-diseased controls (NDC) and donors with Alzheimer's disease (AD) using imaging mass cytometry (IMC) and single nuclear RNA (snRNA) sequencing (> 200,000 nuclei). We found increases in numbers of glia immunostaining for galactosidase beta (> fourfold) and p16 (up to twofold) with AD relative to NDC. Increased glial expression of genes related to senescence was associated with greater β-amyloid load. Prematurely senescent microglia downregulated phagocytic pathways suggesting reduced capacity for β-amyloid clearance. Gene set enrichment and pseudo-time trajectories described extensive DNA double-strand breaks (DSBs), mitochondrial dysfunction and ER stress associated with increased β-amyloid leading to premature senescence in microglia. We replicated these observations with independent AD snRNA-seq datasets. Our results describe a burden of senescent glia with AD that is sufficiently high to contribute to disease progression. These findings support the hypothesis that microglia are a primary target for senolytic treatments in AD.
Topics: Alzheimer Disease; Humans; Cellular Senescence; Aged; Transcriptome; Male; Aged, 80 and over; Female; Microglia; Brain; Amyloid beta-Peptides; Neuroglia
PubMed: 38695952
DOI: 10.1007/s00401-024-02727-9 -
Theranostics 2024Tripeptidyl peptidase II (TPP2) has been proven to be related to human immune and neurological diseases. It is generally considered as a cytosolic protein which forms...
Tripeptidyl peptidase II coordinates the homeostasis of calcium and lipids in the central nervous system and its depletion causes presenile dementia in female mice through calcium/lipid dyshomeostasis-induced autophagic degradation of CYP19A1.
Tripeptidyl peptidase II (TPP2) has been proven to be related to human immune and neurological diseases. It is generally considered as a cytosolic protein which forms the largest known protease complex in eukaryotic cells to operate mostly downstream of proteasomes for degradation of longer peptides. However, this canonical function of TPP2 cannot explain its role in a wide variety of biological and pathogenic processes. The mechanistic interrelationships and hierarchical order of these processes have yet to be clarified. Animals, cells, plasmids, and viruses established and/or used in this study include: TPP2 knockout mouse line, TPP2 conditional knockout mouse lines (different neural cell type oriented), TRE-TPP2 knockin mouse line on the C57BL/6 background; 293T cells with depletion of TPP2, ATF6, IRE1, PERK, SYVN1, UCHL1, ATG5, CEPT1, or CCTα, respectively; 293T cells stably expressing TPP2, TPP2 S449A, TPP2 S449T, or CCTα-KDEL proteins on the TPP2-depleted background; Plasmids for eukaryotic transient expression of rat CYP19A1-Flag, CYP19A1 S118A-Flag, CYP19A1 S118D-Flag, Sac I ML GFP Strand 11 Long, OMMGFP 1-10, G-CEPIA1er, GCAMP2, CEPIA3mt, ACC-GFP, or SERCA1-GFP; AAV2 carrying the expression cassette of mouse CYP19A1-3 X Flag-T2A-ZsGreen. Techniques used in this study include: Flow cytometry, Immunofluorescence (IF) staining, Immunohistochemical (IHC) staining, Luxol fast blue (LFB) staining, β-galactosidase staining, Lipid droplet (LD) staining, Calcium (Ca) staining, Stimulated emission depletion (STED) imaging, Transmission electron microscopic imaging, Two-photon imaging, Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end Labeling (TUNEL) assay, Bromodeoxyuridine (BrdU) assay, Enzymatic activity assay, Proximity ligation assay (PLA), In vivo electrophysiological recording, Long-term potentiation (LTP) recording, Split-GFP-based mitochondria-associated membrane (MAM) detection, Immunoprecipitation (IP), Cellular fractionation, In situ hybridization, Semi-quantitative RT-PCR, Immunoblot, Mass spectrometry-based lipidomics, metabolomics, proteomics, Primary hippocampal neuron culture and Morris water maze (MWM) test. We found that TPP2, independent of its enzymatic activity, plays a crucial role in maintaining the homeostasis of intracellular Ca and phosphatidylcholine (PC) in the central nervous system (CNS) of mice. In consistence with the critical importance of Ca and PC in the CNS, TPP2 gene ablation causes presenile dementia in female mice, which is closely associated with Ca/PC dysregulation-induced endoplasmic reticulum (ER) stress, abnormal autophagic degradation of CYP19A1 (aromatase), and estrogen depletion. This work therefore uncovers a new role of TPP2 in lipogenesis and neurosteroidogenesis which is tightly related to cognitive function of adult female mice. Our study reveals a crucial role of TPP2 in controlling homeostasis of Ca and lipids in CNS, and its deficiency causes sexual dimorphism in dementia. Thus, this study is not only of great significance for elucidating the pathogenesis of dementia and its futural treatment, but also for interpreting the role of TPP2 in other systems and their related disorders.
Topics: Animals; Female; Humans; Mice; Rats; Alzheimer Disease; Aminopeptidases; Aromatase; Calcium; Central Nervous System; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Homeostasis; Lipids; Mice, Inbred C57BL; Mice, Knockout; Serine Endopeptidases
PubMed: 38389851
DOI: 10.7150/thno.92571 -
International Journal of Molecular... Jun 2024Mitochondrial one-carbon metabolism provides carbon units to several pathways, including nucleic acid synthesis, mitochondrial metabolism, amino acid metabolism, and... (Review)
Review
Mitochondrial one-carbon metabolism provides carbon units to several pathways, including nucleic acid synthesis, mitochondrial metabolism, amino acid metabolism, and methylation reactions. Late-onset Alzheimer's disease is the most common age-related neurodegenerative disease, characterised by impaired energy metabolism, and is potentially linked to mitochondrial bioenergetics. Here, we discuss the intersection between the molecular pathways linked to both mitochondrial one-carbon metabolism and Alzheimer's disease. We propose that enhancing one-carbon metabolism could promote the metabolic processes that help brain cells cope with Alzheimer's disease-related injuries. We also highlight potential therapeutic avenues to leverage one-carbon metabolism to delay Alzheimer's disease pathology.
Topics: Alzheimer Disease; Humans; Mitochondria; Carbon; Energy Metabolism; Animals
PubMed: 38928008
DOI: 10.3390/ijms25126302 -
Journal of Advanced Research Dec 2023Synaptic dysfunction is a major contributor to Alzheimeŕs disease (AD) pathogenesis in addition to the formation of neuritic β-amyloid plaques and neurofibrillary... (Review)
Review
BACKGROUND
Synaptic dysfunction is a major contributor to Alzheimeŕs disease (AD) pathogenesis in addition to the formation of neuritic β-amyloid plaques and neurofibrillary tangles of hyperphosphorylated Tau protein. However, how these features contribute to synaptic dysfunction and axonal loss remains unclear. While years of considerable effort have been devoted to gaining an improved understanding of this devastating disease, the unavailability of patient-derived tissues, considerable genetic heterogeneity, and lack of animal models that faithfully recapitulate human AD have hampered the development of effective treatment options. Ongoing progress in human induced pluripotent stem cell (hiPSC) technology has permitted the derivation of patient- and disease-specific stem cells with unlimited self-renewal capacity. These cells can differentiate into AD-affected cell types, which support studies of disease mechanisms, drug discovery, and the development of cell replacement therapies in traditional and advanced cell culture models.
AIM OF REVIEW
To summarize current hiPSC-based AD models, highlighting the associated achievements and challenges with a primary focus on neuron and synapse loss.
KEY SCIENTIFIC CONCEPTS OF REVIEW
We aim to identify how hiPSC models can contribute to understanding AD-associated synaptic dysfunction and axonal loss. hiPSC-derived neural cells, astrocytes, and microglia, as well as more sophisticated cellular organoids, may represent reliable models to investigate AD and identify early markers of AD-associated neural degeneration.
Topics: Animals; Humans; Alzheimer Disease; Induced Pluripotent Stem Cells; Amyloid beta-Peptides; Neurons; Synapses
PubMed: 36646419
DOI: 10.1016/j.jare.2023.01.006 -
Nature Communications Nov 2023The mechanisms that confer cognitive resilience to Alzheimer's Disease (AD) are not fully understood. Here, we describe a neural circuit mechanism underlying this...
The mechanisms that confer cognitive resilience to Alzheimer's Disease (AD) are not fully understood. Here, we describe a neural circuit mechanism underlying this resilience in a familial AD mouse model. In the prodromal disease stage, interictal epileptiform spikes (IESs) emerge during anesthesia in the CA1 and mPFC regions, leading to working memory disruptions. These IESs are driven by inputs from the thalamic nucleus reuniens (nRE). Indeed, tonic deep brain stimulation of the nRE (tDBS-nRE) effectively suppresses IESs and restores firing rate homeostasis under anesthesia, preventing further impairments in nRE-CA1 synaptic facilitation and working memory. Notably, applying tDBS-nRE during the prodromal phase in young APP/PS1 mice mitigates age-dependent memory decline. The IES rate during anesthesia in young APP/PS1 mice correlates with later working memory impairments. These findings highlight the nRE as a central hub of functional resilience and underscore the clinical promise of DBS in conferring resilience to AD pathology by restoring circuit-level homeostasis.
Topics: Mice; Animals; Alzheimer Disease; Midline Thalamic Nuclei; Mice, Transgenic; Deep Brain Stimulation; Cognition; Disease Models, Animal; Amyloid beta-Protein Precursor
PubMed: 37919286
DOI: 10.1038/s41467-023-42721-5 -
Biosensors Sep 2023Alzheimer's disease (AD) is a leading cause of dementia, impacting millions worldwide. However, its complex neuropathologic features and heterogeneous pathophysiology... (Review)
Review
Alzheimer's disease (AD) is a leading cause of dementia, impacting millions worldwide. However, its complex neuropathologic features and heterogeneous pathophysiology present significant challenges for diagnosis and treatment. To address the urgent need for early AD diagnosis, this review focuses on surface-enhanced Raman scattering (SERS)-based biosensors, leveraging the excellent optical properties of nanomaterials to enhance detection performance. These highly sensitive and noninvasive biosensors offer opportunities for biomarker-driven clinical diagnostics and precision medicine. The review highlights various types of SERS-based biosensors targeting AD biomarkers, discussing their potential applications and contributions to AD diagnosis. Specific details about nanomaterials and targeted AD biomarkers are provided. Furthermore, the future research directions and challenges for improving AD marker detection using SERS sensors are outlined.
Topics: Humans; Alzheimer Disease; Nanostructures; Precision Medicine
PubMed: 37754114
DOI: 10.3390/bios13090880 -
International Journal of Molecular... Jul 2023Sigma (σ) receptors are a class of unique proteins with two subtypes: the sigma-1 (σ) receptor which is situated at the mitochondria-associated endoplasmic reticulum... (Review)
Review
Sigma (σ) receptors are a class of unique proteins with two subtypes: the sigma-1 (σ) receptor which is situated at the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), and the sigma-2 (σ) receptor, located in the ER-resident membrane. Increasing evidence indicates the involvement of both σ and σ receptors in the pathogenesis of Alzheimer's disease (AD), and thus these receptors represent two potentially effective biomarkers for emerging AD therapies. The availability of optimal radioligands for positron emission tomography (PET) neuroimaging of the σ and σ receptors in humans will provide tools to monitor AD progression and treatment outcomes. In this review, we first summarize the significance of both receptors in the pathophysiology of AD and highlight AD therapeutic strategies related to the σ and σ receptors. We then survey the potential PET radioligands, with an emphasis on the requirements of optimal radioligands for imaging the σ or σ receptors in humans. Finally, we discuss current challenges in the development of PET radioligands for the σ or σ receptors, and the opportunities for neuroimaging to elucidate the σ and σ receptors as novel biomarkers for early AD diagnosis, and for monitoring of disease progression and AD drug efficacy.
Topics: Humans; Receptors, sigma; Alzheimer Disease; Positron-Emission Tomography; Neuroimaging; Ligands
PubMed: 37569401
DOI: 10.3390/ijms241512025