scholarly journals Simvastatin Therapy Attenuates Memory Deficits that Associate to Brain Monocyte Infiltration in Chronic Hypercholesterolemic ApoE-/- Mice

2020 ◽  
Author(s):  
Nicholas Don-Doncow ◽  
Frank Matthes ◽  
Hana Matuskova ◽  
Sara Rattik ◽  
Lotte Vanherle ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cognitive Decline ◽  
Memory Impairment ◽  
Memory Function ◽  
Memory Deficits ◽  
List Type ◽  
Wild Type ◽  
Lowering Therapy ◽  
Neuro Inflammation ◽  
Cardiovascular Therapeutics

AbstractBackground and PurposeMetabolic and cardiovascular disease is the most prevalent disease burden in the world and risk factor for progressive cognitive decline. Evidence associates cardiovascular risk factors to unfavorable systemic and neuro-inflammation and to cognitive decline. Cardiovascular therapeutics (e.g., statins and antihypertensives) possess immune-modulatory functions in parallel to their cholesterol- or blood pressure (BP)-lowering properties. How their ability to modify immune responses affects cognitive function is unknown.Experimental ApproachBy using flow cytometry, Elisa, qPCR, Western blotting and object recognition tasks, we examined the effect of chronic hypercholesterolemia on inflammation and memory function in Apolipoprotein E (ApoE) knockout mice and normocholesterolemic wild-type mice.Key resultsChronic hypercholesterolemia associated to moderate BP elevations and apparent immune system activation characterized by increases in circulating pro-inflammatory Ly6Chi monocytes in ApoE-/- mice. The persistent low-grade immune activation associated to chronic hypercholesterolemia facilitates the infiltration of pro-inflammatory Ly6Chi monocytes into the brain of aged ApoE-/- but not wild-type mice, linking to memory dysfunction. Therapeutic administration of cholesterol-lowering simvastatin reduced BP, systemic and neuro-inflammation, and the occurrence of memory deficits in aged ApoE-/- mice. BP-lowering therapy alone (i.e. hydralazine) attenuated some neuro-inflammatory signatures but not the occurrence of memory deficits. When administered in combination, it reduced effectiveness of statin therapy in some instances.Conclusions and ImplicationsOur study suggests a link between chronic hypercholesterolemia, myeloid cell activation and neuro-inflammation with memory impairment. Cholesterol-lowering therapy provides effectiveness to attenuate memory impairment and inflammatory events and hence, emerges as safe therapeutic strategy to control hypercholesterolemia-associated memory decline.What is already knowncardiovascular risk factors link to unfavorable systemic and neuro-inflammation and to cognitive declinecardiovascular therapeutics possess immune-modulatory functions in parallel to their principle cholesterol- or blood pressure-lowering propertiesWhat this study addslinks chronic hypercholesterolemia in mice to specific immune responses and the development of memory impairmentfavorable outcomes in respect to neuro-inflammation and memory function in hypercholesterolemic mice after statin therapyClinical significanceopens the door for available CVD therapeutics with long-term safety profiles to managing cognitive dysfunctiontargeted monitoring of inflammatory signature in patients with high cardiovascular burden (surrogate biomarker of cognitive decline)

scholarly journals Simvastatin therapy attenuates memory deficits that associate with brain monocyte infiltration in chronic hypercholesterolemia

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Nicholas Don-Doncow ◽  
Lotte Vanherle ◽  
Frank Matthes ◽  
Sine Kragh Petersen ◽  
Hana Matuskova ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cell Activation ◽  
Memory Function ◽  
Memory Deficits ◽  
Low Grade ◽  
Wild Type ◽  
Cholesterol Lowering ◽  
Immune System Activation ◽  
Lowering Therapy ◽  
Neuro Inflammation

AbstractEvidence associates cardiovascular risk factors with unfavorable systemic and neuro-inflammation and cognitive decline in the elderly. Cardiovascular therapeutics (e.g., statins and anti-hypertensives) possess immune-modulatory functions in parallel to their cholesterol- or blood pressure (BP)-lowering properties. How their ability to modify immune responses affects cognitive function is unknown. Here, we examined the effect of chronic hypercholesterolemia on inflammation and memory function in Apolipoprotein E (ApoE) knockout mice and normocholesterolemic wild-type mice. Chronic hypercholesterolemia that was accompanied by moderate blood pressure elevations associated with apparent immune system activation characterized by increases in circulating pro-inflammatory Ly6Chi monocytes in ApoE-/- mice. The persistent low-grade immune activation that is associated with chronic hypercholesterolemia facilitates the infiltration of pro-inflammatory Ly6Chi monocytes into the brain of aged ApoE-/- but not wild-type mice, and links to memory dysfunction. Therapeutic cholesterol-lowering through simvastatin reduced systemic and neuro-inflammation, and the occurrence of memory deficits in aged ApoE-/- mice with chronic hypercholesterolemia. BP-lowering therapy alone (i.e., hydralazine) attenuated some neuro-inflammatory signatures but not the occurrence of memory deficits. Our study suggests a link between chronic hypercholesterolemia, myeloid cell activation and neuro-inflammation with memory impairment and encourages cholesterol-lowering therapy as safe strategy to control hypercholesterolemia-associated memory decline during ageing.

scholarly journals Case Series Using Montelukast in Patients with Memory Loss and Dementia

2017 ◽  
Vol 11 (1) ◽  
pp. 7-10 ◽  
Author(s):  
Spencer I. Rozin
Keyword(s):  
Receptor Antagonist ◽  
Memory Impairment ◽  
Animal Studies ◽  
Memory Function ◽  
Memory Loss ◽  
Case Series ◽  
Cysteinyl Leukotriene ◽  
Dementia Patients ◽  
Neuro Inflammation ◽  
Memory And Recall

Cognitive decline and dementia are a growing problem as the population ages. Effective therapies to prevent and treat these problems are limited. Neuro-inflammation has been suggested as a cause of dementia [1]. Montelukast is a leukotriene receptor antagonist used to treat seasonal allergies and asthma. It acts as a cysteinyl leukotriene (CysLT1) receptor antagonist blocking the action of leukotrienes and decreasing inflammation [2]. Animal studies have shown that administering Montelukast improves memory function [3]. This case series of patients in a private Internal Medicine practice between 2013-2014 used Montelukast in patients with various levels of memory impairment and dementia. Patients were given Montelukast 80 mg daily in 4 divided doses every 2-3 hours. Memory impaired patients had subjective improvement in the memory and recall. Patients with dementia were noted by family members to be less agitated, but had no memory improvement at the doses used. Montelukast may be useful to treat memory impairment and dementia. Long term use might act as a prophylactic to prevent dementia.

scholarly journals Memory trace superimposition impairs recall in a mouse model of AD

2018 ◽  
Author(s):  
Stefanie Poll ◽  
Lena C. Schmid ◽  
Julia Steffen ◽  
Jens Wagner ◽  
Boris Schmidt ◽  
...  
Keyword(s):  
Mouse Model ◽  
Memory Impairment ◽  
Memory Trace ◽  
Amyloid Β ◽  
Contextual Fear Conditioning ◽  
Early Gene ◽  
Memory Recall ◽  
List Type ◽  
Wild Type

SummaryLearning and memory processes depend on the hippocampus and are impaired in Alzheimer’s disease (AD). Active neuronal ensembles form an engram by encoding information during learning. Their reactivation is required for memory recall. However, it remains unresolved whether the engram in CA1 principal neurons is impaired under AD-like conditions. We used two-photon in vivo imaging to visualize the expression of the immediate early gene c-fos within CA1 neurons during contextual fear conditioning and retrieval. Surprisingly, we identified engrams in wild-type mice and in the mouse model of AD indicating intact memory formation. However, under AD-like conditions engrams were superimposed by a high number of newly recruited fosGFP+ neurons during memory recall. This superimposition resembled the network configuration of wild-type mice exposed to a novel context. Artificial superimposition of the memory trace during recall in wild-type mice was sufficient to induce memory impairment. Thus, we propose superimposition of the CA1 memory trace as a mechanism for memory impairment in a mouse model of AD.HighlightsDecreased fosGFP expression in direct vicinity to amyloid-β plaquesIntact engram in CA1 of APP/PS1 miceImpurity of the retrieval network in CA1 is sufficient to impair memory recallPoll et al. present a novel mechanism for memory impairment in a mouse model of AD. The potential memory trace was found intact in the CA1 region of the hippocampus. However, excessive neuronal activity during retrieval, was superimposing the memory trace in a mouse model of AD.

Mnemonics Usage and Cognitive Decline in Age-Associated Memory Impairment

1997 ◽  
Vol 9 (1) ◽  
pp. 47-56 ◽  
Author(s):  
Gary W. Small ◽  
Asenath La Rue ◽  
Scott Komo ◽  
Andrea Kaplan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Family History ◽  
Cognitive Decline ◽  
Memory Impairment ◽  
Memory Function ◽  
Subjective Memory ◽  
Memory Measure ◽  
History Of

To determine predictors of cognitive deterioration, the authors performed baseline and 1- to 5-year follow-up (mean ± SD = 2.5 ± 1.2 years) neuropsychological assessments on 36 persons (mean age ± SD = 62.1 ± 8.0; range = 50 to 81 years) with age-associated memory impairment. Subjects were recruited from a larger group of volunteers, had minimal medical comorbidity, and 25 of them had a family history of Alzheimer's disease. Baseline age and a subjective memory measure indicating reported frequency of mnemonics usage were significant decline predictors. Subjects reporting more frequent mnemonics use at baseline were more likely to show objective cognitive decline at follow-up. Baseline full-scale IQ, educational level, and family history of Alzheimer's disease failed to predict decline. These findings suggest that although age is the strongest decline predictor in some people with age-associated memory impairment, self-perception of memory function may also predict subsequent cognitive loss.

scholarly journals Non-Alzheimer's disease-related memory impairment and dementia

2013 ◽  
Vol 15 (4) ◽  
pp. 465-473 ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Memory Impairment ◽  
Clinical Symptoms ◽  
Memory Function ◽  
The Elderly ◽  
Memory Deficits ◽  
Common Cause ◽  
Underlying Causes ◽  
Therapeutic Possibilities

Although Alzheimer's disease (AD) is a common cause of memory impairment and dementia in the elderly disturbed memory function is a widespread subjective and/or objective symptom in a variety of medical conditions. The early detection and correct distinction of AD from non-AD memory impairment is critically important to detect possibly treatable and reversible underlying causes. In the context of clinical research, it is crucial to correctly distinguish between AD or non-AD memory impairment in order to build homogenous study populations for the assessment of new therapeutic possibilities. The distinction of AD from non-AD memory impairment may be difficult, especially in mildly affected patients, due to an overlap of clinical symptoms and biomarker alterations between AD and certain non-AD conditions. This review aims to describe recent aspects of the differential diagnosis of AD and non-AD related memory impairment and how these may be considered in the presence of memory deficits.

Verbal and non-verbal recall by depressed and euthymic affective patients

1986 ◽  
Vol 16 (4) ◽  
pp. 789-794 ◽  
Author(s):  
Avraham Calev ◽  
Yaacov Korin ◽  
Baruch Shapira ◽  
Sol Kugelmass ◽  
Bernard Lerer
Keyword(s):  
Memory Impairment ◽  
Lithium Treatment ◽  
Memory Function ◽  
Memory Deficits ◽  
Verbal Recall ◽  
Memory Functioning ◽  
Depressed State ◽  
Differential Deficit ◽  
Drug Free ◽  
Poor Memory

SynopsisThis study uses matched-tasks methodology in order to test memory function in depressed and euthymic patients with major affective disorder. Neither drug-free depressed patients nor lithium-treated euthymic patients show a differential deficit in verbal versus non-verbal recall. However, while euthymic patients show no memory impairment, drug-free depressives do show poor memory functioning. The results support the view that memory deficits observed in affective patients in the depressed state are transient, secondary manifestations of depression and are neither indicative of underlying organic pathology, nor of abnormal hemispheric laterality. This suggests that memory impairment in depression can be treated by treating depressive symptoms, both chemically and behaviourally. The results also support the view that prophylactic lithium treatment has no adverse effects on these memory tasks.

scholarly journals Combining P301L and S320F tau variants produces a novel accelerated model of tauopathy

2019 ◽  
Vol 28 (19) ◽  
pp. 3255-3269 ◽  
Author(s):  
Emily J Koller ◽  
Elsa Gonzalez De La Cruz ◽  
Timothy Machula ◽  
Kristen R Ibanez ◽  
Wen-Lang Lin ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Memory Impairment ◽  
Behavioral Outcomes ◽  
Memory Deficits ◽  
Wild Type ◽  
Robust Model ◽  
Physiological Properties ◽  
Targeted Expression ◽  
Tangle Pathology ◽  
End Stage

Abstract Understanding the biological functions of tau variants can illuminate differential etiologies of Alzheimer’s disease (AD) and primary tauopathies. Though the end-stage neuropathological attributes of AD and primary tauopathies are similar, the etiology and behavioral outcomes of these diseases follow unique and divergent trajectories. To study the divergent physiological properties of tau variants on a uniform immunogenetic background, we created somatic transgenesis CNS models of tauopathy utilizing neonatal delivery of adeno-associated viruses expressing wild-type (WT) or mutant tau in non-transgenic mice. We selected four different tau variants—WT tau associated with AD, P301L mutant tau associated with frontotemporal dementia (FTD), S320F mutant tau associated with Pick’s disease and a combinatorial approach using P301L/S320F mutant tau. CNS-targeted expression of WT and P301L mutant tau results in robust tau hyperphosphorylation without tangle pathology, gradually developing age-progressive memory deficits. In contrast, the S320F variant, especially in combination with P301L, produces an AD-type tangle pathology, focal neuroinflammation and memory impairment on an accelerated time scale. Using the doubly mutated P301L/S320F tau variant, we demonstrate that combining different mutations can have an additive effect on neuropathologies and associated co-morbidities, possibly hinting at involvement of unique functional pathways. Importantly, we also show that overexpression of wild-type tau as well as an FTD-associated tau variant can lead to cognitive deficits even in the absence of tangles. Together, our data highlights the synergistic neuropathologies and associated cognitive and synaptic alterations of the combinatorial tau variant leading to a robust model of tauopathy.

scholarly journals Next generation methodology for updating HA vaccines against emerging human seasonal influenza A(H3N2) viruses

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
James D. Allen ◽  
Ted M. Ross
Keyword(s):  
Influenza Virus ◽  
Immune Responses ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Influenza Viruses ◽  
Next Generation ◽  
Virus Infections ◽  
Wild Type ◽  
Influenza Hemagglutinin ◽  
H3n2 Influenza

AbstractWhile vaccines remain the best tool for preventing influenza virus infections, they have demonstrated low to moderate effectiveness in recent years. Seasonal influenza vaccines typically consist of wild-type influenza A and B viruses that are limited in their ability to elicit protective immune responses against co-circulating influenza virus variant strains. Improved influenza virus vaccines need to elicit protective immune responses against multiple influenza virus drift variants within each season. Broadly reactive vaccine candidates potentially provide a solution to this problem, but their efficacy may begin to wane as influenza viruses naturally mutate through processes that mediates drift. Thus, it is necessary to develop a method that commercial vaccine manufacturers can use to update broadly reactive vaccine antigens to better protect against future and currently circulating viral variants. Building upon the COBRA technology, nine next-generation H3N2 influenza hemagglutinin (HA) vaccines were designed using a next generation algorithm and design methodology. These next-generation broadly reactive COBRA H3 HA vaccines were superior to wild-type HA vaccines at eliciting antibodies with high HAI activity against a panel of historical and co-circulating H3N2 influenza viruses isolated over the last 15 years, as well as the ability to neutralize future emerging H3N2 isolates.

scholarly journals γ-PGA-Rich Chungkookjang, Short-Term Fermented Soybeans: Prevents Memory Impairment by Modulating Brain Insulin Sensitivity, Neuro-Inflammation, and the Gut–Microbiome–Brain Axis

Foods ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 221
Author(s):  
Do-Youn Jeong ◽  
Myeong Seon Ryu ◽  
Hee-Jong Yang ◽  
Sunmin Park
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Gut Microbiome ◽  
Memory Impairment ◽  
Memory Function ◽  
Bacillus Species ◽  
Fermented Foods ◽  
Short Term ◽  
Brain Insulin ◽  
Brain Insulin Resistance

Fermented soybean paste is an indigenous food for use in cooking in East and Southeast Asia. Korea developed and used its traditional fermented foods two thousand years ago. Chungkookjang has unique characteristics such as short-term fermentation (24–72 h) without salt, and fermentation mostly with Bacilli. Traditionally fermented chungkookjang (TFC) is whole cooked soybeans that are fermented predominantly by Bacillus species. However, Bacillus species are different in the environment according to the regions and seasons due to the specific bacteria. Bacillus species differently contribute to the bioactive components of chungkookjang, resulting in different functionalities. In this review, we evaluated the production process of poly-γ-glutamic acid (γ-PGA)-rich chungkookjang fermented with specific Bacillus species and their effects on memory function through the modulation of brain insulin resistance, neuroinflammation, and the gut–microbiome–brain axis. Bacillus species were isolated from the TFC made in Sunchang, Korea, and they included Bacillus (B.) subtilis, B. licheniformis, and B. amyloliquefaciens. Chungkookjang contains isoflavone aglycans, peptides, dietary fiber, γ-PGA, and Bacillus species. Chungkookjangs made with B. licheniformis and B. amyloliquefaciens have higher contents of γ-PGA, and they are more effective for improving glucose metabolism and memory function. Chungkookjang has better efficacy for reducing inflammation and oxidative stress than other fermented soy foods. Insulin sensitivity is improved, not only in systemic organs such as the liver and adipose tissues, but also in the brain. Chungkookjang intake prevents and alleviates memory impairment induced by Alzheimer’s disease and cerebral ischemia. This review suggests that the intake of chungkookjang (20–30 g/day) rich in γ-PGA acts as a synbiotic in humans and promotes memory function by suppressing brain insulin resistance and neuroinflammation and by modulating the gut–microbiome–brain axis.

scholarly journals Next Generation of Computationally Optimized Broadly Reactive HA Vaccines Elicited Cross-Reactive Immune Responses and Provided Protection against H1N1 Virus Infection

Vaccines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 793
Author(s):  
Ying Huang ◽  
Monique S. França ◽  
James D. Allen ◽  
Hua Shi ◽  
Ted M. Ross
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Immune Responses ◽  
H1n1 Virus ◽  
Influenza Virus Infection ◽  
H1n1 Influenza ◽  
Influenza Viruses ◽  
Next Generation ◽  
Wild Type ◽  
Influenza A H1n1

Vaccination is the best way to prevent influenza virus infections, but the diversity of antigenically distinct isolates is a persistent challenge for vaccine development. In order to conquer the antigenic variability and improve influenza virus vaccine efficacy, our research group has developed computationally optimized broadly reactive antigens (COBRAs) in the form of recombinant hemagglutinins (rHAs) to elicit broader immune responses. However, previous COBRA H1N1 vaccines do not elicit immune responses that neutralize H1N1 virus strains in circulation during the recent years. In order to update our COBRA vaccine, two new candidate COBRA HA vaccines, Y2 and Y4, were generated using a new seasonal-based COBRA methodology derived from H1N1 isolates that circulated during 2013–2019. In this study, the effectiveness of COBRA Y2 and Y4 vaccines were evaluated in mice, and the elicited immune responses were compared to those generated by historical H1 COBRA HA and wild-type H1N1 HA vaccines. Mice vaccinated with the next generation COBRA HA vaccines effectively protected against morbidity and mortality after infection with H1N1 influenza viruses. The antibodies elicited by the COBRA HA vaccines were highly cross-reactive with influenza A (H1N1) pdm09-like viruses isolated from 2009 to 2021, especially with the most recent circulating viruses from 2019 to 2021. Furthermore, viral loads in lungs of mice vaccinated with Y2 and Y4 were dramatically reduced to low or undetectable levels, resulting in minimal lung injury compared to wild-type HA vaccines following H1N1 influenza virus infection.

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