Fluoxetine Protects against Dendritic Spine Loss in Middle-aged APPswe/PSEN1dE9 Double Transgenic Alzheimer’s Disease Mice

Background: Studies have suggested that cognitive impairment in Alzheimer’s disease (AD) is associated with dendritic spine loss, especially in the hippocampus. Fluoxetine (FLX) has been shown to improve cognition in the early stage of AD and to be associated with diminishing synapse degeneration in the hippocampus. However, little is known about whether FLX affects the pathogenesis of AD in the middle-tolate stage and whether its effects are correlated with the amelioration of hippocampal dendritic dysfunction. Previously, it has been observed that FLX improves the spatial learning ability of middleaged APP/PS1 mice. Objective: In the present study, we further characterized the impact of FLX on dendritic spines in the hippocampus of middle-aged APP/PS1 mice. Results: It has been found that the numbers of dendritic spines in dentate gyrus (DG), CA1 and CA2/3 of hippocampus were significantly increased by FLX. Meanwhile, FLX effectively attenuated hyperphosphorylation of tau at Ser396 and elevated protein levels of postsynaptic density 95 (PSD-95) and synapsin-1 (SYN-1) in the hippocampus. Conclusion: These results indicated that the enhanced learning ability observed in FLX-treated middle-aged APP/PS1 mice might be associated with remarkable mitigation of hippocampal dendritic spine pathology by FLX and suggested that FLX might be explored as a new strategy for therapy of AD in the middle-to-late stage.

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Synapses and Dendritic Spines as Pathogenic Targets in Alzheimer’s Disease

Neural Plasticity ◽

10.1155/2012/247150 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 49

Author(s):

Wendou Yu ◽

Bingwei Lu

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Learning And Memory ◽

Dendritic Spines ◽

Dendritic Spine ◽

Molecular Mechanisms ◽

Excitatory Synapses ◽

Dendritic Shaft ◽

Spine Pathology ◽

Dynamic Structures

Synapses are sites of cell-cell contacts that transmit electrical or chemical signals in the brain. Dendritic spines are protrusions on dendritic shaft where excitatory synapses are located. Synapses and dendritic spines are dynamic structures whose plasticity is thought to underlie learning and memory. No wonder neurobiologists are intensively studying mechanisms governing the structural and functional plasticity of synapses and dendritic spines in an effort to understand and eventually treat neurological disorders manifesting learning and memory deficits. One of the best-studied brain disorders that prominently feature synaptic and dendritic spine pathology is Alzheimer’s disease (AD). Recent studies have revealed molecular mechanisms underlying the synapse and spine pathology in AD, including a role for mislocalized tau in the postsynaptic compartment. Synaptic and dendritic spine pathology is also observed in other neurodegenerative disease. It is possible that some common pathogenic mechanisms may underlie the synaptic and dendritic spine pathology in neurodegenerative diseases.

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Attracting New Investigators to Alzheimer’s Disease Research: Outcomes of Increased Funding and Outreach

The Gerontologist ◽

10.1093/geront/gnaa056 ◽

2020 ◽

Author(s):

Pragati Katiyar ◽

Catherine Nagy ◽

Samir Sauma ◽

Marie A Bernard

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Aging ◽

Early Stage ◽

Research Field ◽

National Institutes Of Health ◽

Fiscal Year ◽

Disease Research ◽

Nih Funding ◽

The Impact

Abstract Since 2015, the National Institute on Aging (NIA), National Institutes of Health (NIH), has experienced significant increases in funding for Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD). This analysis assesses the impact of these funds on expanding the AD/ADRD workforce. NIA administered 860 awards to 695 AD/ADRD R01 awardees during fiscal year 2015–2018. Twenty-nine percent of awardees were new or early-stage investigators, while 38% were new to the AD/ADRD research field (NTF). Among these NTFs, 59% were established investigators, that is, experts with NIH funding in another discipline but new to AD/ADRD research. Awards were further analyzed to determine the focus of their research based on International Alzheimer’s Disease Research Portfolio (IADRP) categories. Forty-six percent were focused on Molecular Pathogenesis and Physiology. Other IADRP categories, including Diagnosis, Assessment, and Disease Monitoring and Translational Research and Clinical Interventions, represented 5%–15% of awards. Significantly, NTF investigators received 50%, 42%, and 70% of the total grants awarded in Population Studies, Dementia Care, and Brain Aging, respectively, suggesting that NTF investigators are filling research gaps. While these results suggest that enhanced funding is associated with recruitment of new talent, opportunities for further growth remain, particularly related to care, caregiving, and health disparities.

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Possible selves and illness: A comparison of individuals with Parkinson's disease, early-stage Alzheimer's disease, and healthy older adults

International Journal of Behavioral Development ◽

10.1080/01650250143000526 ◽

2003 ◽

Vol 27 (1) ◽

pp. 1-11 ◽

Cited By ~ 29

Author(s):

Leslie D. Frazier ◽

Victoria Cotrell ◽

Karen Hooker

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Parkinson’S Disease ◽

Alzheimer's Disease ◽

Parkinson's Disease ◽

Possible Selves ◽

Early Stage ◽

Healthy Older Adults ◽

Patient Groups ◽

The Impact

This study examined how future self-representations are affected by two different chronic illnesses, one focused on cognitive losses, early-stage Alzheimer's disease (AD), and one focused on physical losses, Parkinson's disease (PD). The impact of illness on possible selves (perceptions of self in the future) was made salient by a comparison with healthy older adults in order to better understand developmental issues in later life. Findings show that although there were no differences in the total number of domains reported by the groups, specific domains were reported differently by patient groups and all domains were likely to become infused with illness. As expected, patient groups had less self-efficacy and lower outcome expectancies for their future selves, and PD patients reported less distance from their feared selves. Although these findings are intuitive, this is the first empirical effort to document the impact of illness on older adults' self-representations. Group differences are explained in terms of disease context, and the importance of possible selves and self-regulatory functions as therapeutic mechanisms for adaptation to illness are emphasised.

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Performance of healthy elderly with Alzheimer's disease at an early stage in executive function and language

European Psychiatry ◽

10.1016/s0924-9338(11)72205-2 ◽

2011 ◽

Vol 26 (S2) ◽

pp. 498-498

Author(s):

M.T. Santos ◽

G.C. Couto ◽

J.C. Achieri ◽

C.A. Júnior

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

The Elderly ◽

Screening Tests ◽

Healthy Elderly ◽

Initial Stage ◽

Significant Difference ◽

Common Causes ◽

The Impact

Dementia are increasingly prevalent in population. The most common causes of dementia is Alzheimer's disease (AD). Screening tests have been used for the premature diagnosis of Alzheimer Disease (AD), specifically in the executive functions and language, which are compromised at an initial stage. However, the necessity standardized means and validated for our middle, to show oneself a pressing subject.ObjectiveTo analyze the impact of the length of sentences in the abstraction of proverbs in the Screening Test for Alzheimer's disease with Proverbs (TRDAP), healthy elderly and with Alzheimer's disease at early stage.MethodSurvey document in the database, analyzing the responses of the elderly (abstract or concrete interpretation of proverbs), relating the length of sentences (sayings) of stage B of TRDAP with the diagnosis of Alzheimer's disease and the interference of age and schooling.ResultsHealthy older people showed greater capacity for abstraction than those with AD. There was Significant differences, in the sayings 1 (p = 0.033) and 2 (p = 0.001), corresponding to lower sentences, which did not occur with the proverb 3. As for age no verified significant difference among the healthy and only saying 3 in AD patients, however schooling differenced the healthy.ConclusionElderly with Alzheimer's disease at an initial stage have lower performance in the comprehension of ambiguous sentences, interpretation and abstraction of proverbs, corroborating with the data of the literature. The size of these sentences appears to be inversely proportional to the correctness of interpretation in elderly patients with and without AD.

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Intraneuronal APP and extracellular Aβ independently cause dendritic spine pathology in transgenic mouse models of Alzheimer’s disease

Acta Neuropathologica ◽

10.1007/s00401-015-1421-4 ◽

2015 ◽

Vol 129 (6) ◽

pp. 909-920 ◽

Cited By ~ 28

Author(s):

Chengyu Zou ◽

Elena Montagna ◽

Yuan Shi ◽

Finn Peters ◽

Lidia Blazquez-Llorca ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mouse ◽

Mouse Models ◽

Dendritic Spine ◽

Transgenic Mouse Models ◽

Spine Pathology

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Analyzing dendritic spine pathology in Alzheimer’s disease: problems and opportunities

Acta Neuropathologica ◽

10.1007/s00401-015-1449-5 ◽

2015 ◽

Vol 130 (1) ◽

pp. 1-19 ◽

Cited By ~ 71

Author(s):

Mario M. Dorostkar ◽

Chengyu Zou ◽

Lidia Blazquez-Llorca ◽

Jochen Herms

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dendritic Spine ◽

Spine Pathology

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Speech- and Language-Based Classification of Alzheimer’s Disease: A Systematic Review

Bioengineering ◽

10.3390/bioengineering9010027 ◽

2022 ◽

Vol 9 (1) ◽

pp. 27

Author(s):

Inês Vigo ◽

Luis Coelho ◽

Sara Reis

Keyword(s):

Systematic Review ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Best Practices ◽

Early Stage ◽

Low Cost ◽

Clinical Stage ◽

Invasive Procedure ◽

The Impact

Background: Alzheimer’s disease (AD) has paramount importance due to its rising prevalence, the impact on the patient and society, and the related healthcare costs. However, current diagnostic techniques are not designed for frequent mass screening, delaying therapeutic intervention and worsening prognoses. To be able to detect AD at an early stage, ideally at a pre-clinical stage, speech analysis emerges as a simple low-cost non-invasive procedure. Objectives: In this work it is our objective to do a systematic review about speech-based detection and classification of Alzheimer’s Disease with the purpose of identifying the most effective algorithms and best practices. Methods: A systematic literature search was performed from Jan 2015 up to May 2020 using ScienceDirect, PubMed and DBLP. Articles were screened by title, abstract and full text as needed. A manual complementary search among the references of the included papers was also performed. Inclusion criteria and search strategies were defined a priori. Results: We were able: to identify the main resources that can support the development of decision support systems for AD, to list speech features that are correlated with the linguistic and acoustic footprint of the disease, to recognize the data models that can provide robust results and to observe the performance indicators that were reported. Discussion: A computational system with the adequate elements combination, based on the identified best-practices, can point to a whole new diagnostic approach, leading to better insights about AD symptoms and its disease patterns, creating conditions to promote a longer life span as well as an improvement in patient quality of life. The clinically relevant results that were identified can be used to establish a reference system and help to define research guidelines for future developments.

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A Review of Oxidative Stress Products and Related Genes in Early Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-210497 ◽

2021 ◽

pp. 1-25

Author(s):

Federica Cioffi ◽

Rayan Hassan Ibrahim Adam ◽

Ruchi Bansal ◽

Kerensa Broersen

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Early Stage ◽

Disease Status ◽

Diagnostic Value ◽

Oxidation Products ◽

Protein Levels ◽

Stress Levels

Oxidative stress is associated with the progression of Alzheimer’s disease (AD). Reactive oxygen species can modify lipids, DNA, RNA, and proteins in the brain. The products of their peroxidation and oxidation are readily detectable at incipient stages of disease. Based on these oxidation products, various biomarker-based strategies have been developed to identify oxidative stress levels in AD. Known oxidative stress-related biomarkers include lipid peroxidation products F2-isoprostanes, as well as malondialdehyde and 4-hydroxynonenal which both conjugate to specific amino acids to modify proteins, and DNA or RNA oxidation products 8-hydroxy-2’-deoxyguanosine (8-OHdG) and 8-hydroxyguanosine (8-OHG), respectively. The inducible enzyme heme oxygenase type 1 (HO-1) is found to be upregulated in response to oxidative stress-related events in the AD brain. While these global biomarkers for oxidative stress are associated with early-stage AD, they generally poorly differentiate from other neurodegenerative disorders that also coincide with oxidative stress. Redox proteomics approaches provided specificity of oxidative stress-associated biomarkers to AD pathology by the identification of oxidatively damaged pathology-specific proteins. In this review, we discuss the potential combined diagnostic value of these reported biomarkers in the context of AD and discuss eight oxidative stress-related mRNA biomarkers in AD that we newly identified using a transcriptomics approach. We review these genes in the context of their reported involvement in oxidative stress regulation and specificity for AD. Further research is warranted to establish the protein levels and their functionalities as well as the molecular mechanisms by which these potential biomarkers are involved in regulation of oxidative stress levels and their potential for determination of oxidative stress and disease status of AD patients.

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Impact of Hyperhomocysteinemia and Different Dietary Interventions on Cognitive Performance in a Knock-in Mouse Model for Alzheimer’s Disease

Nutrients ◽

10.3390/nu12113248 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3248

Author(s):

Hendrik Nieraad ◽

Natasja de Bruin ◽

Olga Arne ◽

Martine C. J. Hofmann ◽

Mike Schmidt ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Cognitive Performance ◽

Early Stage ◽

Amyloid Β ◽

Dietary Interventions ◽

Homocysteic Acid ◽

Plaque Deposition ◽

The Impact

Background: Hyperhomocysteinemia is considered a possible contributor to the complex pathology of Alzheimer’s disease (AD). For years, researchers in this field have discussed the apparent detrimental effects of the endogenous amino acid homocysteine in the brain. In this study, the roles of hyperhomocysteinemia driven by vitamin B deficiency, as well as potentially beneficial dietary interventions, were investigated in the novel AppNL-G-F knock-in mouse model for AD, simulating an early stage of the disease. Methods: Urine and serum samples were analyzed using a validated LC-MS/MS method and the impact of different experimental diets on cognitive performance was studied in a comprehensive behavioral test battery. Finally, we analyzed brain samples immunohistochemically in order to assess amyloid-β (Aβ) plaque deposition. Results: Behavioral testing data indicated subtle cognitive deficits in AppNL-G-F compared to C57BL/6J wild type mice. Elevation of homocysteine and homocysteic acid, as well as counteracting dietary interventions, mostly did not result in significant effects on learning and memory performance, nor in a modified Aβ plaque deposition in 35-week-old AppNL-G-F mice. Conclusion: Despite prominent Aβ plaque deposition, the AppNL-G-F model merely displays a very mild AD-like phenotype at the investigated age. Older AppNL-G-F mice should be tested in order to further investigate potential effects of hyperhomocysteinemia and dietary interventions.

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Candidate Alzheimer’s Disease Biomarker miR-483-5p Lowers TAU Phosphorylation by Direct ERK1/2 Repression

International Journal of Molecular Sciences ◽

10.3390/ijms22073653 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3653

Author(s):

Siranjeevi Nagaraj ◽

Andrew Want ◽

Katarzyna Laskowska-Kaszub ◽

Aleksandra Fesiuk ◽

Sara Vaz ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Erk Pathway ◽

Neurofibrillary Pathology ◽

Protein Levels ◽

Disease Biomarker ◽

Extracellular Signal ◽

Novel Target

MicroRNAs have been demonstrated as key regulators of gene expression in the etiology of a range of diseases including Alzheimer’s disease (AD). Recently, we identified miR-483-5p as the most upregulated miRNA amongst a panel of miRNAs in blood plasma specific to prodromal, early-stage Alzheimer’s disease patients. Here, we investigated the functional role of miR-483-5p in AD pathology. Using TargetScan and miRTarBase, we identified the microtubule-associated protein MAPT, often referred to as TAU, and the extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2), known to phosphorylate TAU, as predicted direct targets of miR-483-5p. Employing several functional assays, we found that miR-483-5p regulates ERK1 and ERK2 at both mRNA and protein levels, resulting in lower levels of phosphorylated forms of both kinases. Moreover, miR-483-5p-mediated repression of ERK1/2 resulted in reduced phosphorylation of TAU protein at epitopes associated with TAU neurofibrillary pathology in AD. These results indicate that upregulation of miR-483-5p can decrease phosphorylation of TAU via ERK pathway, representing a compensatory neuroprotective mechanism in AD pathology. This miR-483-5p/ERK1/TAU axis thus represents a novel target for intervention in AD.

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