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Aging & Mental Health Jul 2024The current study aimed to evaluate the relationship between subjective cognitive complaints (SCC) and compensatory strategy (CS) use in a diverse sample of non-Latinx...
OBJECTIVES
The current study aimed to evaluate the relationship between subjective cognitive complaints (SCC) and compensatory strategy (CS) use in a diverse sample of non-Latinx White (NLW), Black, and Latinx American older adults.
METHOD
807 older adults ( = 65.38, 62.7% female) were recruited through Amazon's Mechanical Turk (MTurk) and Qualtrics Panel to complete questionnaires on SCC and CS use. Kruskall-Wallis tests were used to evaluate differences in SCC across groups given non-normal distributions. Analysis of variance (ANOVA) was used to evaluate group differences in CS use. The PROCESS macro for SPSS was used to examine whether demographic factors moderated the relationship between SCC and CS use.
RESULTS
NLWs reported higher levels of SCC and greater overall use of CS in comparison to Latinx and Black individuals. Several demographic and psychosocial factors including age, ethno-racial group, education, and anxiety level were found to be associated with CS use. Education was found to moderate the association between SCC and CS use.
CONCLUSION
Inconsistent with prior studies, our study found that NLWs reported the highest levels of SCC. CS were used across all racial/ethnic groups, but the frequency of CS use may be impacted by education level. While all education groups increased their CS in response to higher levels of SCC, this increase was more substantial for those with lower levels of education. Future work should consider individuals' cultural and educational background when examining SCC and/or developing CS-based intervention for the aging population.
PubMed: 38952264
DOI: 10.1080/13607863.2024.2367060 -
Physical Chemistry Chemical Physics :... Jul 2024The hallmark of amyloidosis, such as Alzheimer's disease and Parkinson's disease, is the deposition of amyloid fibrils in various internal organs. The onset of the...
The hallmark of amyloidosis, such as Alzheimer's disease and Parkinson's disease, is the deposition of amyloid fibrils in various internal organs. The onset of the disease is related to the strength of cytotoxicity caused by toxic amyloid species. Furthermore, amyloid fibrils show polymorphism, where some types of fibrils are cytotoxic while others are not. It is thus essential to understand the molecular mechanism of cytotoxicity, part of which is caused by the interaction between amyloid polymorphic fibrils and cell membranes. Here, using amyloid polymorphs of hen egg white lysozyme, which is associated with hereditary systemic amyloidosis, showing different levels of cytotoxicity and liposomes of DMPC and DMPG, changes in the secondary structure of the polymorphs and the structural state of phospholipid membranes caused by the interaction were investigated using vacuum-ultraviolet circular dichroism (VUVCD) and Laurdan fluorescence measurements, respectively. Analysis has shown that the more cytotoxic polymorph increases the antiparallel β-sheet content and causes more disorder in the membrane structure while the other less cytotoxic polymorph shows the opposite structural changes and causes less structural disorder in the membrane. These results suggest a close correlation between the structural properties of amyloid fibrils and the degree of structural disorder of phospholipid membranes, both of which are involved in the fundamental process leading to amyloid cytotoxicity.
PubMed: 38952218
DOI: 10.1039/d4cp00965g -
Annals of Clinical and Translational... Jul 2024To examine the associations of renin-angiotensin system (RAS) inhibitor use with postmortem brain insulin signaling and neuropathology.
OBJECTIVE
To examine the associations of renin-angiotensin system (RAS) inhibitor use with postmortem brain insulin signaling and neuropathology.
METHODS
Among Religious Orders Study participants, 150 deceased and autopsied older individuals (75 with diabetes matched to 75 without by age at death, sex, and education) had measurements of insulin receptor substrate-1 (IRS-1) and RAC-alpha serine/threonine protein kinase (AKT1) collected in the prefrontal cortex using ELISA and immunohistochemistry. Alzheimer's disease (AD), brain infarcts, and cerebral vessel pathology data were assessed by systematic neuropathologic evaluations. RAS inhibitor use was determined based on visual inspection of medication containers during study visits. The associations of RAS inhibitor use with brain insulin signaling measures and neuropathology were examined using adjusted regression analyses.
RESULTS
Of the 90 RAS inhibitor users (54 with diabetes), 65 had used only angiotensin-converting enzyme inhibitors, 11 only angiotensin II receptor blockers, and 14 used both. RAS inhibitor use was associated with lower pTAKT1/total AKT1, but not with pSIRS-1/total IRS-1 or the density of cells stained positive for pS IRS-1. RAS inhibitor use was not associated with the level of global AD pathology or amyloid beta burden, but it was associated with a lower tau-neurofibrillary tangle density. Additionally, we found a significant interaction between diabetes and RAS inhibitors on tangle density. Furthermore, AKT1 phosphorylation partially mediated the association of RAS inhibitor use with tau tangle density. Lastly, RAS inhibitor use was associated with more atherosclerosis, but not with other cerebral blood vessel pathologies or cerebral infarcts.
INTERPRETATION
Late-life RAS inhibitor use may be associated with lower brain AKT1 phosphorylation and fewer neurofibrillary tangles.
PubMed: 38952081
DOI: 10.1002/acn3.52132 -
Aging Cell Jul 2024Alzheimer's disease (AD) is a neurodegenerative disorder associated with behavioral and cognitive impairments. Unfortunately, the drugs the Food and Drug Administration...
Alzheimer's disease (AD) is a neurodegenerative disorder associated with behavioral and cognitive impairments. Unfortunately, the drugs the Food and Drug Administration currently approved for AD have shown low effectiveness in delaying the progression of the disease. The focus has shifted to non-pharmacological interventions (NPIs) because of the challenges associated with pharmacological treatments for AD. One such intervention is environmental enrichment (EE), which has been reported to restore cognitive decline associated with AD effectively. However, the therapeutic mechanisms by which EE improves symptoms associated with AD remain unclear. Therefore, this study aimed to reveal the mechanisms underlying the alleviating effects of EE on AD symptoms using histological, proteomic, and neurotransmitter-related analyses. Wild-type (WT) and 5XFAD mice were maintained in standard housing or EE conditions for 4 weeks. First, we confirmed the mitigating effects of EE on cognitive impairment in an AD animal model. Then, histological analysis revealed that EE reduced Aβ accumulation, neuroinflammation, neuronal death, and synaptic loss in the AD brain. Moreover, proteomic analysis by liquid chromatography-tandem mass spectrometry showed that EE enhanced synapse- and neurotransmitter-related networks and upregulated synapse- and neurotransmitter-related proteins in the AD brain. Furthermore, neurotransmitter-related analyses showed an increase in acetylcholine and serotonin concentrations as well as a decrease in polyamine concentration in the frontal cortex and hippocampus of 5XFAD mice raised under EE conditions. Our findings demonstrate that EE restores cognitive impairment by alleviating AD pathology and regulating synapse-related proteins and neurotransmitters. Our study provided neurological evidence for the application of NPIs in treating AD.
PubMed: 38952076
DOI: 10.1111/acel.14231 -
Cell Biochemistry and Function Jul 2024This review rigorously investigates the early cerebral changes associated with Alzheimer's disease, which manifest long before clinical symptoms arise. It presents... (Review)
Review
This review rigorously investigates the early cerebral changes associated with Alzheimer's disease, which manifest long before clinical symptoms arise. It presents evidence that the dysregulation of calcium (Ca) homeostasis, along with mitochondrial dysfunction and aberrant autophagic processes, may drive the disease's progression during its asymptomatic, preclinical stage. Understanding the intricate molecular interplay that unfolds during this critical period offers a window into identifying novel therapeutic targets, thereby advancing the treatment of neurodegenerative disorders. The review delves into both established and emerging insights into the molecular alterations precipitated by the disruption of Ca balance, setting the stage for cognitive decline and neurodegeneration.
Topics: Humans; Alzheimer Disease; Mitochondria; Calcium; Mitophagy; Autophagy; Animals; Hemostasis; Homeostasis
PubMed: 38951992
DOI: 10.1002/cbf.4085 -
Alzheimer's Research & Therapy Jun 2024Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are associated with self-reported problems with cognition as well as risk for Alzheimer's disease...
BACKGROUND
Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are associated with self-reported problems with cognition as well as risk for Alzheimer's disease and related dementias (ADRD). Overlapping symptom profiles observed in cognitive disorders, psychiatric disorders, and environmental exposures (e.g., head injury) can complicate the detection of early signs of ADRD. The interplay between PTSD, head injury, subjective (self-reported) cognitive concerns and genetic risk for ADRD is also not well understood, particularly in diverse ancestry groups.
METHODS
Using data from the U.S. Department of Veterans Affairs (VA) Million Veteran Program (MVP), we examined the relationship between dementia risk factors (APOE ε4, PTSD, TBI) and subjective cognitive concerns (SCC) measured in individuals of European (n = 140,921), African (n = 15,788), and Hispanic (n = 8,064) ancestry (EA, AA, and HA, respectively). We then used data from the VA electronic medical record to perform a retrospective survival analysis evaluating PTSD, TBI, APOE ε4, and SCC and their associations with risk of conversion to ADRD in Veterans aged 65 and older.
RESULTS
PTSD symptoms (B = 0.50-0.52, p < 1E-250) and probable TBI (B = 0.05-0.19, p = 1.51E-07 - 0.002) were positively associated with SCC across all three ancestry groups. APOE ε4 was associated with greater SCC in EA Veterans aged 65 and older (B = 0.037, p = 1.88E-12). Results of Cox models indicated that PTSD symptoms (hazard ratio [HR] = 1.13-1.21), APOE ε4 (HR = 1.73-2.05) and SCC (HR = 1.18-1.37) were positively associated with risk for ADRD across all three ancestry groups. In the EA group, probable TBI also contributed to increased risk of ADRD (HR = 1.18).
CONCLUSIONS
The findings underscore the value of SCC as an indicator of ADRD risk in Veterans 65 and older when considered in conjunction with other influential genetic, clinical, and demographic risk factors.
Topics: Humans; Veterans; Stress Disorders, Post-Traumatic; Male; Female; Aged; Apolipoprotein E4; Dementia; Risk Factors; United States; Brain Injuries, Traumatic; Aged, 80 and over; Retrospective Studies
PubMed: 38951900
DOI: 10.1186/s13195-024-01512-w -
Alzheimer's Research & Therapy Jun 2024The Amyloid precursor protein (APP) is a transmembrane glycoprotein from which amyloid-β (Aβ) peptides are generated after proteolytic cleavage. Aβ peptides are the... (Review)
Review
The Amyloid precursor protein (APP) is a transmembrane glycoprotein from which amyloid-β (Aβ) peptides are generated after proteolytic cleavage. Aβ peptides are the main constituent of amyloid plaques in Alzheimer's Disease (AD). The physiological functions of APP in the human adult brain are very diverse including intracellular signaling, synaptic and neuronal plasticity, and cell adhesion, among others. There is growing evidence that APP becomes dysfunctional in AD and that this dyshomeostasis may impact several APP functions beyond Aβ generation. The vast majority of current anti-amyloid approaches in AD have focused on reducing the synthesis of Aβ or increasing the clearance of brain Aβ aggregates following a paradigm in which Aβ plays a solo in APP dyshomeostasis. A wider view places APP at the center stage in which Aβ is an important, but not the only, factor involved in APP dyshomeostasis. Under this paradigm, APP dysfunction is universal in AD, but with some differences across different subtypes. Little is known about how to approach APP dysfunction therapeutically beyond anti-Aβ strategies. In this review, we will describe the role of APP dyshomeostasis in AD beyond Aβ and the potential therapeutic strategies targeting APP.
Topics: Humans; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Amyloid beta-Peptides; Brain
PubMed: 38951839
DOI: 10.1186/s13195-024-01504-w -
Alzheimer's & Dementia : the Journal of... Jul 2024Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the...
INTRODUCTION
Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi-site study, using a predefined hypothesis.
METHODS
We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes.
RESULTS
CVR and MoCA were positively associated, and this relationship was reproduced at all analysis sites. CVR was found to be positively associated with executive function.
DISCUSSION
The predefined hypothesis on the association between CVR and a global cognitive score was validated in three independent analysis sites, providing support for CVR as a biomarker in VCID.
HIGHLIGHTS
This study measured a novel functional index of small arteries referred to as cerebrovascular reactivity (CVR). CVR was positively associated with global cognition in older adults. This finding was observed in three independent cohorts at three sites. Our statistical analysis plan was predefined before beginning data collection.
PubMed: 38951718
DOI: 10.1002/alz.13888 -
Nature Cell Biology Jul 2024α-Synuclein (α-Syn) aggregation is closely associated with Parkinson's disease neuropathology. Physiologically, α-Syn promotes synaptic vesicle (SV) clustering and...
α-Synuclein (α-Syn) aggregation is closely associated with Parkinson's disease neuropathology. Physiologically, α-Syn promotes synaptic vesicle (SV) clustering and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly. However, the underlying structural and molecular mechanisms are uncertain and it is not known whether this function affects the pathological aggregation of α-Syn. Here we show that the juxtamembrane region of vesicle-associated membrane protein 2 (VAMP2)-a component of the SNARE complex that resides on SVs-directly interacts with the carboxy-terminal region of α-Syn through charged residues to regulate α-Syn's function in clustering SVs and promoting SNARE complex assembly by inducing a multi-component condensed phase of SVs, α-Syn and other components. Moreover, VAMP2 binding protects α-Syn against forming aggregation-prone oligomers and fibrils in these condensates. Our results suggest a molecular mechanism that maintains α-Syn's function and prevents its pathological amyloid aggregation, the failure of which may lead to Parkinson's disease.
PubMed: 38951706
DOI: 10.1038/s41556-024-01456-1 -
Communications Chemistry Jun 2024The neuroprotective transcription factor nuclear receptor-related 1 (Nurr1) has shown great promise as a therapeutic target in Parkinson's and Alzheimer's disease as...
The neuroprotective transcription factor nuclear receptor-related 1 (Nurr1) has shown great promise as a therapeutic target in Parkinson's and Alzheimer's disease as well as multiple sclerosis but high-quality chemical tools for pharmacological target validation of Nurr1 are rare. We have employed the weak Nurr1 modulator amodiaquine (AQ) and AQ-derived fragments as templates to design a new Nurr1 agonist chemotype by scaffold hopping and fragment growing strategies. Systematic structural optimization of this scaffold yielded Nurr1 agonists with nanomolar potency and binding affinity. Comprehensive in vitro profiling revealed efficient cellular target engagement and compliance with the highest probe criteria. In human midbrain organoids bearing a Parkinson-driving LRRK2 mutation, a novel Nurr1 agonist rescued tyrosine hydroxylase expression highlighting the potential of the new Nurr1 modulator chemotype as lead and as a chemical tool for biological studies.
PubMed: 38951694
DOI: 10.1038/s42004-024-01224-0