Increased RyR2 open probability induces neuronal hyperactivity and memory loss with or without Alzheimer's disease–causing gene mutations

Abstract:: Recent studies have proven that the purinergic signaling pathway plays a key role in neurotransmission and neuromodulation, and is involved in various neurodegenerative diseases and psychiatric disorders. With the characterization of the subtypes of receptors in purinergic signaling, i.e. the P1 (adenosine), P2X (ion channel) and P2Y (G protein-coupled), more attentions were paid to the pathophysiology and therapeutic potential of purinergic signaling in central nervous system disorders. Alzheimer’s disease (AD) is a progressive and deadly neurodegenerative disease that is characterized by memory loss, cognitive impairment and dementia. However, as drug development aimed to prevent or control AD follows a series of failures in recent years, more researchers focused on the neuroprotection-related mechanisms such as purinergic signaling in AD patients to find a potential cure. This article reviews the recent discoveries of purinergic signaling in AD, summaries the potential agents as modulators for the receptors of purinergic signaling in AD related research and treatments. Thus, our paper provided an insight for purinergic signaling in the development of anti-AD therapies.

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Many caregivers of persons with memory loss or Alzheimer's disease are unaware of the abilities of their persons with AD to recall their drugs and medical histories

Dementia ◽

10.1177/1471301218820969 ◽

2018 ◽

pp. 147130121882096

Author(s):

Thomas A Ala ◽

GaToya Simpson ◽

Marshall T Holland ◽

Vajeeha Tabassum ◽

Maithili Deshpande ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Memory Loss ◽

Medical Histories ◽

With Memory

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Induced Pluripotent Stem Cell-Derived Neural Precursors Improve Memory, Synaptic and Pathological Abnormalities in a Mouse Model of Alzheimer’s Disease

Cells ◽

10.3390/cells10071802 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1802

Author(s):

Enrique Armijo ◽

George Edwards ◽

Andrea Flores ◽

Jorge Vera ◽

Mohammad Shahnawaz ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Symptoms ◽

Memory Loss ◽

Amyloid Β ◽

Cerebral Atrophy ◽

Brain Inflammation ◽

Neural Precursors ◽

Model Of Alzheimer’S Disease ◽

Induced Pluripotent

Alzheimer’s disease (AD) is the most common type of dementia in the elderly population. The disease is characterized by progressive memory loss, cerebral atrophy, extensive neuronal loss, synaptic alterations, brain inflammation, extracellular accumulation of amyloid-β (Aβ) plaques, and intracellular accumulation of hyper-phosphorylated tau (p-tau) protein. Many recent clinical trials have failed to show therapeutic benefit, likely because at the time in which patients exhibit clinical symptoms the brain is irreversibly damaged. In recent years, induced pluripotent stem cells (iPSCs) have been suggested as a promising cell therapy to recover brain functionality in neurodegenerative diseases such as AD. To evaluate the potential benefits of iPSCs on AD progression, we stereotaxically injected mouse iPSC-derived neural precursors (iPSC-NPCs) into the hippocampus of aged triple transgenic (3xTg-AD) mice harboring extensive pathological abnormalities typical of AD. Interestingly, iPSC-NPCs transplanted mice showed improved memory, synaptic plasticity, and reduced AD brain pathology, including a reduction of amyloid and tangles deposits. Our findings suggest that iPSC-NPCs might be a useful therapy that could produce benefit at the advanced clinical and pathological stages of AD.

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Promoting Conversations About Cognitive Decline Between Older Adults and Primary Care Providers

Innovation in Aging ◽

10.1093/geroni/igaa057.513 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 157-158

Author(s):

Benjamin Olivari ◽

Christopher Taylor ◽

Nia Reed ◽

Lisa McGuire

Keyword(s):

Alzheimer’S Disease ◽

Primary Care ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Cognitive Decline ◽

Chronic Conditions ◽

Memory Loss ◽

Primary Care Providers ◽

Subjective Cognitive Decline ◽

Care Providers

Abstract Alzheimer’s disease and related dementias often begin with symptoms of mild memory loss, eventually leading to more severe cognitive impairment, functional impairment, and ultimately, death. Data from the Behavioral Risk Factor Surveillance System core questions related to chronic diseases and from the cognitive decline optional module on subjective cognitive decline (SCD) from the years 2015-2018 were aggregated across the participating 50 states, D.C., and Puerto Rico for this analysis. Among U.S. adults aged 65 years and older, only 39.8% (95%CI=37.6-42.1) of those experiencing SCD reported discussing their SCD symptoms with a healthcare provider. The prevalence of discussing SCD symptoms with a provider was higher among those with at least one chronic condition than among those with no chronic conditions. 30.7% (28.6-32.8) of those aged 65 years and older reported that their SCD led to functional limitations and 28.8% (26.5-31.2) needed assistance with day-to-day activities. For patients aged 65 years and older, Welcome to Medicare visits and Medicare Annual Wellness Visits are critically underutilized primary care access points. Primary care providers can manage chronic conditions, cognitive health, and initiate referrals for testing. Efforts to promote the use of toolkits and diagnostic codes that are available to primary care providers to initiate conversations about memory loss with patients may be utilized to improve detection, diagnosis, and planning for memory problems. Discussions may lead to earlier detection and diagnosis of cognitive impairment, such as Alzheimer’s disease, or other treatable conditions such as delirium or pressure in the brain and avoid costly hospitalizations.

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ADeditome provides the genomic landscape of A-to-I RNA editing in Alzheimer’s disease

Briefings in Bioinformatics ◽

10.1093/bib/bbaa384 ◽

2021 ◽

Author(s):

Sijia Wu ◽

Mengyuan Yang ◽

Pora Kim ◽

Xiaobo Zhou

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rna Editing ◽

Memory Loss ◽

Brain Regions ◽

Disease Stage ◽

Mirna Regulation ◽

Annotation Database ◽

Functional Annotations ◽

Genomic Landscape

Abstract A-to-I RNA editing, contributing to nearly 90% of all editing events in human, has been reported to involve in the pathogenesis of Alzheimer’s disease (AD) due to its roles in brain development and immune regulation, such as the deficient editing of GluA2 Q/R related to cell death and memory loss. Currently, there are urgent needs for the systematic annotations of A-to-I RNA editing events in AD. Here, we built ADeditome, the annotation database of A-to-I RNA editing in AD available at https://ccsm.uth.edu/ADeditome, aiming to provide a resource and reference for functional annotation of A-to-I RNA editing in AD to identify therapeutically targetable genes in an individual. We detected 1676 363 editing sites in 1524 samples across nine brain regions from ROSMAP, MayoRNAseq and MSBB. For these editing events, we performed multiple functional annotations including identification of specific and disease stage associated editing events and the influence of editing events on gene expression, protein recoding, alternative splicing and miRNA regulation for all the genes, especially for AD-related genes in order to explore the pathology of AD. Combing all the analysis results, we found 108 010 and 26 168 editing events which may promote or inhibit AD progression, respectively. We also found 5582 brain region-specific editing events with potentially dual roles in AD across different brain regions. ADeditome will be a unique resource for AD and drug research communities to identify therapeutically targetable editing events. Significance: ADeditome is the first comprehensive resource of the functional genomics of individual A-to-I RNA editing events in AD, which will be useful for many researchers in the fields of AD pathology, precision medicine, and therapeutic researches.

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Main Plant Extracts’ Active Properties Effective on Scopolamine-Induced Memory Loss

American Journal of Alzheimer s Disease & Other Dementias® ◽

10.1177/1533317517715906 ◽

2017 ◽

Vol 32 (7) ◽

pp. 418-428 ◽

Cited By ~ 3

Author(s):

Ioana-Miruna Balmus ◽

Alin Ciobica

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Plant Extracts ◽

Current Knowledge ◽

Symptomatic Relief ◽

Memory Loss ◽

Current Treatment ◽

General Effect ◽

Function Loss ◽

Theory Research

Alzheimer’s disease leads to progressive cognitive function loss, which may impair both intellectual capacities and psychosocial aspects. Although the current knowledge points to a multifactorial character of Alzheimer’s disease, the most issued pathological hypothesis remains the cholinergic theory. The main animal model used in cholinergic theory research is the scopolamine-induced memory loss model. Although, in some cases, a temporary symptomatic relief can be obtained through targeting the cholinergic or glutamatergic neurotransmitter systems, no current treatment is able to stop or slow cognitive impairment. Many potentially successful therapies are often blocked by the blood–brain barrier since it exhibits permeability only for several classes of active molecules. However, the plant extracts’ active molecules are extremely diverse and heterogeneous regarding the biochemical structure. In this way, many active compounds constituting the recently tested plant extracts may exhibit the same general effect on acetylcholine pathway, but on different molecular ground, which can be successfully used in Alzheimer’s disease adjuvant therapy.

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Isovitexin modulates autophagy in Alzheimer’s disease via miR-107 signalling

Translational Neuroscience ◽

10.1515/tnsci-2020-0109 ◽

2020 ◽

Vol 11 (1) ◽

pp. 391-401

Author(s):

Jiang Cheng ◽

Guowei Wang ◽

Na Zhang ◽

Fang Li ◽

Lina Shi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Memory Loss ◽

The Elderly ◽

Tnf Α ◽

Autophagic Process ◽

Molecular Signals ◽

Ad Mouse Model ◽

Mtor Signalling

AbstractBackground:Alzheimer’s disease (AD) is an ultimately fatal, degenerative brain disease in the elderly people. In the current work, we assessed the defensive capability of isovitexin (IVX) through an intracerebroventricular injection of streptozotocin (STZ)-induced AD mouse model.Methods:Mice were separated into four cohorts: sham-operated control mice; STZ-intoxicated Alzheimer’s mice; IVX cohort, IVX + STZ; and Ant-107 cohort, antagomiR-107 + IVX/STZ as in the IVX cohort.Results:The outcomes indicated that IVX administration ameliorated spatial memory loss and blunted a cascade of neuro-noxious episodes – including increased amyloid-beta (Aβ) and degraded myelin basic protein burden, neuroinflammation (represented by elevated caspase-1, TNF-α and IL-6 levels) and autophagic dysfunction (represented by altered LC3-II, Atg7 and beclin-1 expressions) – via the inhibition of PI3K/Akt/mTOR signalling axis. We considered the question of whether the epigenetic role of microRNA-107 (miR-107) has any impact on these events, by using antagomiR-107.Conclusion:This probing underscored that miR-107 could be a pivotal regulatory button in the activation of molecular signals linked with the beneficial autophagic process and anti-inflammatory activities in relation to IVX treatment. Hence, this report exemplifies that IVX could guard against Aβ toxicity and serve as an effectual treatment for patients afflicted with AD.

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Case of early-onset Alzheimer’s disease with atypical manifestation

General Psychiatry ◽

10.1136/gpsych-2020-100283 ◽

2021 ◽

Vol 34 (1) ◽

pp. e100283

Author(s):

Lin Zhu ◽

Limin Sun ◽

Lin Sun ◽

Shifu Xiao

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Manifestation ◽

Early Onset ◽

Short Term Memory ◽

Brain Mri ◽

Memory Loss ◽

Amyloid Β ◽

Amyloid Β Protein ◽

Fluent Aphasia

Short-term memory decline is the typical clinical manifestation of Alzheimer’s disease (AD). However, early-onset AD usually has atypical symptoms and may get misdiagnosed. In the present case study, we reported a patient who experienced symptoms of memory loss with progressive non-fluent aphasia accompanied by gradual social withdrawal. He did not meet the diagnostic criteria of AD based on the clinical manifestation and brain MRI. However, his cerebrospinal fluid examination showed a decreased level of beta-amyloid 42, and increased total tau and phosphorylated tau. Massive amyloid β-protein deposition by 11C-Pittsburgh positron emission tomography confirmed the diagnosis of frontal variant AD. This case indicated that early-onset AD may have progressive non-fluent aphasia as the core manifestation. The combination of individual and precision diagnosis would be beneficial for similar cases.

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The Role of Oxidative Stress-Induced Epigenetic Alterations in Amyloid-βProduction in Alzheimer’s Disease

Oxidative Medicine and Cellular Longevity ◽

10.1155/2015/604658 ◽

2015 ◽

Vol 2015 ◽

pp. 1-13 ◽

Cited By ~ 50

Author(s):

Li Zuo ◽

Benjamin T. Hemmelgarn ◽

Chia-Chen Chuang ◽

Thomas M. Best

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Beta ◽

Treatment Options ◽

Memory Loss ◽

The United States ◽

Traditional Medicines ◽

Progressive Neurodegeneration ◽

Antioxidant Supplements

An increasing number of studies have proposed a strong correlation between reactive oxygen species (ROS)-induced oxidative stress (OS) and the pathogenesis of Alzheimer’s disease (AD). With over five million people diagnosed in the United States alone, AD is the most common type of dementia worldwide. AD includes progressive neurodegeneration, followed by memory loss and reduced cognitive ability. Characterized by the formation of amyloid-beta (Aβ) plaques as a hallmark, the connection between ROS and AD is compelling. Analyzing the ROS response of essential proteins in the amyloidogenic pathway, such as amyloid-beta precursor protein (APP) and beta-secretase (BACE1), along with influential signaling programs of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and c-Jun N-terminal kinase (JNK), has helped visualize the path between OS and Aβoverproduction. In this review, attention will be paid to significant advances in the area of OS, epigenetics, and their influence on Aβplaque assembly. Additionally, we aim to discuss available treatment options for AD that include antioxidant supplements, Asian traditional medicines, metal-protein-attenuating compounds, and histone modifying inhibitors.

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