Alzheimer’s Disease: Models and Molecular Mechanisms Informing Disease and Treatments

Bioengineering, Journal Year: 2024, Volume and Issue: 11(1), P. 45 - 45

Published: Jan. 1, 2024

Alzheimer’s Disease (AD) is a complex neurodegenerative disease resulting in progressive loss of memory, language and motor abilities caused by cortical hippocampal degeneration. This review captures the landscape understanding AD pathology, diagnostics, current therapies. Two major mechanisms direct pathology: (1) accumulation amyloid β (Aβ) plaque (2) tau-derived neurofibrillary tangles (NFT). The most common variants Aβ pathway APP, PSEN1, PSEN2 are largely responsible for early-onset (EOAD), while MAPT, APOE, TREM2 ABCA7 have modifying effect on late-onset (LOAD). More recent studies implicate chaperone proteins degrading AD. Several tests, such as cognitive function, brain imaging, cerebral spinal fluid (CSF) blood used diagnosis. Additionally, several biomarkers seem to unique specific combination expression could potentially be improved, less invasive diagnostics. In addition genetic perturbations, environmental influences, altered gut microbiome signatures, affect Effective treatments been challenging develop. Currently, there FDA approved drugs (cholinesterase inhibitors, Aß-targeting antibodies an NMDA antagonist) that mitigate rate decline symptoms distress.

Language: Английский

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Atrophy of hippocampal subfields and amygdala nuclei in subjects with mild cognitive impairment progressing to Alzheimer's disease

Heliyon, Journal Year: 2024, Volume and Issue: 10(6), P. e27429 - e27429

Published: March 1, 2024

The hippocampus and amygdala are the first brain regions to show early signs of Alzheimer's Disease (AD) pathology. AD is preceded by a prodromal stage known as Mild Cognitive Impairment (MCI), crucial crossroad in clinical progression disease. topographical development has been subject extended investigation. However, it still largely unknown how transition from MCI affects specific hippocampal subregions. present study set answer that question. We analyzed data 223 subjects: 75 healthy controls, 52 individuals with MCI, 96 patients obtained ADNI. group was further divided into two subgroups depending on whether 48 months following diagnosis either remained stable (N = 21) or progressed 31). A MANCOVA test evaluated differences volume distinct subregions magnetic resonance images. Subsequently, stepwise linear discriminant analysis (LDA) determined which combination imaging parameters most effective predicting conversion AD. predictive performance assessed through Receiver Operating Characteristic analysis. displayed widespread subregional atrophy. who showed selective atrophy subiculum tail compared individuals, were undistinguishable controls. Converter amygdala's accessory basal, central, cortical nuclei. LDA identified lateral basal nuclei significant predictors returned sensitivity value 0.78 specificity 0.62. These findings highlight importance targeted assessments help dissect pathophysiological transition.

Language: Английский

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Unraveling brain diseases: The promise of brain-on-a-chip models

Journal of Neuroscience Methods, Journal Year: 2024, Volume and Issue: 405, P. 110105 - 110105

Published: March 7, 2024

Brain disorders, encompassing a wide spectrum of neurological and psychiatric conditions, present formidable challenge in modern medicine. Despite decades research, the intricate complexity human brain still eludes comprehensive understanding, impeding development effective treatments. Recent advancements microfluidics tissue engineering have led to innovative platforms known as "Brain-on-a-Chip" (BoC) i.e., advanced vitro systems that aim replicate microenvironment with highest possible fidelity. This technology offers promising test-bed for studying disorders at cellular network levels, providing insights into disease mechanisms, drug screening, and, perspective, personalized therapeutic strategies. In this review, we provide an overview BoC models developed over years model understand onset progression some most severe terms incidence debilitation (stroke, Parkinson's, Alzheimer's, epilepsy). We also report cutting-edge approaches whose effects were evaluated by means these technologies. Finally, discuss potential challenges, future perspectives models.

Language: Английский

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A longitudinal cohort study demonstrating the beneficial effect of moderate consumption of green tea and coffee on the prevention of dementia: The JPHC Saku Mental Health Study

Journal of Alzheimer s Disease, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Background While the preventive effects of green tea and coffee on cognitive decline have been demonstrated, their long-term cognition remain unclear. Objective This study aims to investigate effect consumption in middle age prevention dementia. Methods population-based cohort included 1155 participants (aged 44–66 1995). Participants’ was assessed using questionnaires 1995 2000. Their levels were neuropsychologically evaluated 2025–2015. Logistic regression analyses conducted with significant (defined as multi-domain more severe conditions) dependent variable. Stratified also by sex age. Results Individuals who consumed 2–3 cups daily had a significantly reduced risk (OR = 0.56, 95%CI: 0.35–0.91) after adjusting potential confounders. However, this not 4 or cups. protective particularly observed males 0.38, 0.19–0.76). A reduction individuals consuming one 0.54, 0.34–0.84) older subjects (median [53 years old] 1995) same fully adjusted model, but entire sample. Conclusions Our findings suggest that moderate midlife may beneficial preventing dementia, males. The be advantageous for individuals.

Language: Английский

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Sex-related differences in genetically determined Alzheimer’s disease

Frontiers in Aging Neuroscience, Journal Year: 2025, Volume and Issue: 17

Published: March 4, 2025

We reviewed the literature on sex differences in genetically determined Alzheimer’s disease (AD), focusing autosomal dominant AD (ADAD), Down syndrome-associated (DSAD), and APOE4 homozygosity, particularly regarding penetrance, symptom onset clinical progression, trajectories for markers of amyloidosis (A), tau pathology (T) neurodegeneration (N). Data suggests that onset, AT(N) biomarker are typically subtle populations. Noteworthy exceptions, such as increased later stages females while similar cognitive outcomes, suggest a potential differential reserve warrants further investigation. Additionally, interaction between APOE genotype reveals complex multifaceted effects DSAD, with implications ADAD remain underexplored. The smaller observed compared to sporadic offer insights into different underlying mechanisms Future research should prioritize sex-specific investigations AD, refining methodologies. This includes prioritizing longitudinal designs, adjustment key confounders, adherence guidelines.

Language: Английский

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Commonly prescribed multi‐medication therapies exert sex‐specific effects on Alzheimer's disease pathology and metabolomic profiles in App^NL‐G‐F mice: Implications for personalized therapeutics in aging

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(3)

Published: March 1, 2025

Abstract INTRODUCTION Polypharmacy is common among older adults and people with dementia. Multi‐medication therapy poses risks of harm but also targets comorbidities risk factors associated dementia, offering therapeutic potential. METHODS We evaluated the effects two polypharmacy regimens monotherapies on male female App NL‐G‐F knock‐in mice. assessed functional, emotional, cognitive outcomes;amyloid pathology; serum metabolomics profiles. RESULTS A combination metoprolol, simvastatin, aspirin, paracetamol, citalopram improved memory, reduced amyloid burden neuroinflammation, modulated AD‐associated metabolomic signatures in mice, negligible Substituting cardiovascular drugs impacted emotional domains worsened predominantly In males, could not explain effects, suggesting drug synergy, whereas certain monotherapy were lost when combined. DISCUSSION This study uncovers sex‐specific an AD model, identifying mechanisms biomarkers that can guide gender‐specific use medicines dementia prevention management. Highlights Two combinations show pathology Metoprolol+simvastatin+aspirin+paracetamol+citalopram improves memory Replacing metoprolol simvastatin enalapril atorvastatin eliminates benefits mice impairs Selected produce only partially outcomes combinations. Metabolomic pathways indicate possible for evaluating effectiveness safety personalized therapies aging

Language: Английский

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Auditory sensory deprivation induced by noise exposure exacerbates cognitive decline in a mouse model of Alzheimer’s disease

eLife, Journal Year: 2021, Volume and Issue: 10

Published: Oct. 26, 2021

Although association between hearing impairment and dementia has been widely documented by epidemiological studies, the role of auditory sensory deprivation in cognitive decline remains to be fully understood. To address this issue we investigated impact loss on onset time-course an animal model Alzheimer's disease (AD), that is 3×Tg-AD mice underlying mechanisms. We found induced noise exposure before phenotype manifested caused persistent synaptic morphological alterations cortex. This was associated with earlier hippocampal dysfunction, increased tau phosphorylation, neuroinflammation, redox imbalance, along anticipated memory deficits compared expected neurodegenerative phenotype. Our data suggest a mouse AD more vulnerable central damage shows reduced ability counteract noise-induced detrimental effects, which accelerates onset.

Language: Английский

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Estradiol and Estrogen-like Alternative Therapies in Use: The Importance of the Selective and Non-Classical Actions

Biomedicines, Journal Year: 2022, Volume and Issue: 10(4), P. 861 - 861

Published: April 6, 2022

Estrogen is one of the most important female sex hormones, and indispensable for reproduction. However, its role much wider. Among others, due to neuroprotective effects, estrogen protects brain against dementia complications traumatic injury. Previously, it was used mainly as a therapeutic option influencing menstrual cycle treating menopausal symptoms. Unfortunately, hormone replacement therapy might be associated with detrimental side such increased risk stroke breast cancer, raising concerns about safety. Thus, tissue-selective non-classical analogues have become focus interest. Here, we review current knowledge effects in broader sense, possibility using selective estrogen-receptor modulators (SERMs), downregulators (SERDs), phytoestrogens, activators non-genomic estrogen-like signaling (ANGELS) molecules treatment.

Language: Английский

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The Interaction Between NF-κB and Estrogen in Alzheimer’s Disease

Molecular Neurobiology, Journal Year: 2022, Volume and Issue: 60(3), P. 1515 - 1526

Published: Dec. 13, 2022

Language: Английский

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Biophysical models applied to dementia patients reveal links between geographical origin, gender, disease duration, and loss of neural inhibition

Alzheimer s Research & Therapy, Journal Year: 2024, Volume and Issue: 16(1)

Published: April 11, 2024

Abstract Background The hypothesis of decreased neural inhibition in dementia has been sparsely studied functional magnetic resonance imaging (fMRI) data across patients with different subtypes, and the role social demographic heterogeneities on this remains to be addressed. Methods We inferred regional by fitting a biophysical whole-brain model (dynamic mean field realistic inter-areal connectivity) fMRI from 414 participants, including Alzheimer’s disease, behavioral variant frontotemporal dementia, controls. then investigated effect disease condition, clinical variables local inhibitory feedback, variable related maintenance balanced excitation/inhibition. Results Decreased feedback was modeling results patients, specific brain areas presenting neurodegeneration. This loss correlated positively years showed differences regarding gender geographical origin patients. correctly reproduced known disease-related changes connectivity. Conclusions suggest critical link between abnormal circuit-level excitability levels, grey matter observed reorganization connectivity, while highlighting sensitivity underlying mechanism patient population.

Language: Английский

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