Follow‐up evaluation of cognitive function in the randomized Alzheimer's Disease Anti‐inflammatory Prevention Trial and its Follow‐up Study

Breitner, John C.S.; Baker, Laura D.; Drye, Lea T.; Evans, Denis A.; Lyketsos, Constantine G.; Ryan, Laurie; Zandi, Peter P.; Saucedo, Hector Hernandez; Anau, Jane; Cholerton, Brenna

doi:10.1016/j.jalz.2014.03.009

Cited by 75 publications

(28 citation statements)

References 23 publications

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“…For example, when tested in 3×Tg-AD [80] and Tg2576 mice [81] ibuprofen reduced Aβ plaques load and Aβ 42 levels. But when evaluated for their therapeutic effect against AD in clinical studies, NSAIDs treatment failed to enhance the cognitive function in AD patients [82–84]. Further studies are required to explain such inconsistencies and to confirm the effect of NSAIDs in AD.…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Screening for Identification of Blood-Brain Barrier Integrity Enhancers: A Drug Repurposing Opportunity to Rectify Vascular Amyloid Toxicity

Qosa

Mohamed

Rihani

et al. 2016

JAD

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The blood-brain barrier (BBB) is a dynamic interface that maintains brain homeostasis and protects it from free entry of chemicals, toxins and drugs. The barrier function of the BBB is maintained mainly by capillary endothelial cells that physically separate brain from blood. Several neurological diseases, such as Alzheimer’s disease (AD), are known to disrupt BBB integrity. In this study, a high-throughput screening (HTS) was developed to identify drugs that rectify/protect BBB integrity from vascular amyloid toxicity associated with AD progression. Assessing Lucifer Yellow permeation across in-vitro BBB model composed from mouse brain endothelial cells (bEnd3) grown on 96-well plate inserts was used to screen 1280 compounds of Sigma LOPAC®1280 library for modulators of bEnd3 monolayer integrity. HTS identified 62 compounds as disruptors, and 50 compounds as enhancers of the endothelial barrier integrity. From these 50 enhancers, 7 FDA approved drugs were identified with EC50 values ranging from 0.76–4.56 μM. Of these 7 drugs, five were able to protect bEnd3-based BBB model integrity against amyloid toxicity. Furthermore, to test the translational potential to humans, the 7 drugs were tested for their ability to rectify the disruptive effect of Aβ in the human endothelial cell line hCMEC/D3. Only 3 (etodolac, granisetron and beclomethasone) out of the 5 effective drugs in the bEnd3-based BBB model demonstrated a promising effect to protect the hCMEC/D3-based BBB model integrity. These drugs are compelling candidates for repurposing as therapeutic agents that could rectify dysfunctional BBB associated with AD.

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Section: Discussionmentioning

confidence: 99%

High-Throughput Screening for Identification of Blood-Brain Barrier Integrity Enhancers: A Drug Repurposing Opportunity to Rectify Vascular Amyloid Toxicity

Qosa

Mohamed

Rihani

et al. 2016

JAD

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“…These findings strengthened the notion that glial activation and peripheral immune cell infiltration in the brain is neurotoxic and contributes to ALS, as it was previously reported for multiple sclerosis and spinal cord injury ( DiSabato et al , 2016 ; Ransohoff, 2016 ). Hence, it came as both surprise and disappointment that a large number of ALS clinical trials found no protection provided by various anti-inflammatory agents, similar to trials in other neurodegenerative diseases and traumatic brain injury ( Adapt-Fs, 2015 ; Russo and McGavern, 2016 ; Petrov et al , 2017 ). Multiple reasons for these failures likely exist.…”

Section: Introductionmentioning

confidence: 98%

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

Béland

Markovinović

Jakovac

et al. 2020

Brain Communications

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Despite wide genetic, environmental and clinical heterogeneity in amyotrophic lateral sclerosis, a rapidly fatal neurodegenerative disease targeting motoneurons, neuroinflammation is a common finding. It is marked by local glial activation, T cell infiltration and systemic immune system activation. The immune system has a prominent role in the pathogenesis of various chronic diseases, hence some of them, including some types of cancer, are successfully targeted by immunotherapeutic approaches. However, various anti-inflammatory or immunosuppressive therapies in amyotrophic lateral sclerosis have failed. This prompted increased scrutiny over the immune-mediated processes underlying amyotrophic lateral sclerosis. Perhaps the biggest conundrum is that amyotrophic lateral sclerosis pathogenesis exhibits features of three otherwise distinct immune dysfunctions –excessive inflammation, autoimmunity and inefficient immune responses. Epidemiological and genome-wide association studies show only minimal overlap between amyotrophic lateral sclerosis and autoimmune diseases, so excessive inflammation is usually thought to be secondary to protein aggregation, mitochondrial damage or other stresses. In contrast, several recently characterized amyotrophic lateral sclerosis-linked mutations, including those in TBK1, OPTN, CYLD and C9orf72, could lead to inefficient immune responses and/or damage pile-up, suggesting that an innate immunodeficiency may also be a trigger and/or modifier of this disease. In such cases, nonselective immunosuppression would further restrict neuroprotective immune responses. Here we discuss multiple layers of immune-mediated neuroprotection and neurotoxicity in amyotrophic lateral sclerosis. Particular focus is placed on individual patient mutations that directly or indirectly affect the immune system, and the mechanisms by which these mutations influence disease progression. The topic of immunity in amyotrophic lateral sclerosis is timely and relevant, because it is one of the few common and potentially malleable denominators in this heterogenous disease. Importantly, amyotrophic lateral sclerosis progression has recently been intricately linked to patient T cell and monocyte profiles, as well as polymorphisms in cytokine and chemokine receptors. For this reason, precise patient stratification based on immunophenotyping will be crucial for efficient therapies.

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“…Substantial evidence from laboratory and epidemiologic studies has suggested that anti-inflammatory medication, especially NSAIDs, can defer or prevent AD occurrence. However, recent meta-analyses concluded that ADAPT and ADAPT-FS [29,105] did not support the use of NSAIDs for AD prevention among dementia-free individuals. The ADAPT study was designed to evaluate the efficacy of naproxen, a non-selective cyclooxygenase (COX) inhibitor, and celecoxib, a selective COX-2 inhibitor, in treating AD [105].…”

Section: Anti-inflammatory Therapy For Ad (1)mentioning

confidence: 99%

“…Many reasons have been proposed for the discrepancies between the findings of observational studies and ADAPT. These include the choice of specific NSAIDs, duration of treatment, ApoE ε4 allele, age, disease stage, and speed of disease progression [27,29,105,106]. …”

Section: Anti-inflammatory Therapy For Ad (1)mentioning

confidence: 99%

“…NSAIDs showed no clinical effects on cognitive outcomes in patients with prodromal symptoms or dementia of AD [4,27,28]. Furthermore, NSAID treatment for 1–3 years did not prevent or delay the onset of AD in elderly healthy individuals with a family history of AD, which was investigated by follow-up for 5–7 years after termination of the treatment, according to the Alzheimer’s Disease Anti-Inflammatory Prevention Trial (ADAPT) and follow-up study (ADAPT-FS) [4,29–31]. In contrast, Vlad et al [32] prospectively assessed the effects on AD risk of NSAID use in subjects aged 50 years and older, free of AD at baseline, and found that long-term (>5 years) NSAID users had a lower risk of AD than non-NSAID users.…”

Section: Introductionmentioning

confidence: 99%

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Cytokines and Cytokine Receptors Involved in the Pathogenesis of Alzheimers Disease

Nagae

Araki

Shimoda

et al. 2016

J Clin Cell Immunol

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Inflammatory mechanisms are implicated in the pathology of Alzheimer’s disease (AD). However, it is unclear whether inflammatory alterations are a cause or consequence of neurodegeneration leading to dementia. Clarifying this issue would provide valuable insight into the early diagnosis and therapeutic management of AD. To address this, we compared the mRNA expression profiles of cytokines in the brains of AD patients with “non-demented individuals with AD pathology” and non-demented healthy control (ND) individuals. “Non-demented individuals with AD pathology” are referred to as high pathology control (HPC) individuals that are considered an intermediate subset between AD and ND. HPC represents a transition between normal aging and early stage of AD, and therefore, is useful for determining whether neuroinflammation is a cause or consequence of AD pathology. We observed that immunological conditions that produce cytokines in the HPC brain were more representative of ND than AD. To validate these result, we investigated the expression of inflammatory mediators at the protein level in postmortem brain tissues. We examined the protein expression of tumor necrosis factor (TNF)α and its receptors (TNFRs) in the brains of AD, HPC, and ND individuals. We found differences in soluble TNFα and TNFRs expression between AD and ND groups and between AD and HPC groups. Expression in the temporal cortex was lower in the AD brains than HPC and ND. Our findings indicate that alterations in immunological conditions involving TNFR-mediated signaling are not the primary events initiating AD pathology, such as amyloid plaques and tangle formation. These may be early events occurring along with synaptic and neuronal changes or later events caused by these changes. In this review, we emphasize that elucidating the temporal expression of TNFα signaling molecules during AD is important to understand the selective tuning of these pathways required to develop effective therapeutic strategies for AD.

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Follow‐up evaluation of cognitive function in the randomized Alzheimer's Disease Anti‐inflammatory Prevention Trial and its Follow‐up Study

Cited by 75 publications

References 23 publications

High-Throughput Screening for Identification of Blood-Brain Barrier Integrity Enhancers: A Drug Repurposing Opportunity to Rectify Vascular Amyloid Toxicity

High-Throughput Screening for Identification of Blood-Brain Barrier Integrity Enhancers: A Drug Repurposing Opportunity to Rectify Vascular Amyloid Toxicity

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

Cytokines and Cytokine Receptors Involved in the Pathogenesis of Alzheimers Disease

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