scholarly journals Long-term dynamics of aberrant neuronal activity in Alzheimer’s disease

2019 ◽  
Author(s):  
V. Korzhova ◽  
P. Marinković ◽  
P. M. Goltstein ◽  
J. Herms ◽  
S. Liebscher
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Activity ◽  
Calcium Imaging ◽  
Amyloid Plaque ◽  
Activity Levels ◽  
Highly Active ◽  
Over Time

SummaryAlzheimer’s disease (AD) is associated with aberrant neuronal activity levels. How those activity alterations emerge and how stable they are over time in vivo, however, remains elusive to date. To address these questions we chronically recorded the activity from identified neurons in cortex of awake APPPS1 transgenic mice and their non-transgenic littermates over the course of 4 weeks by means of calcium imaging. Surprisingly, aberrant neuronal activity was very stable over time. Moreover, we identified a slow progressive gain of activity of former intermediately active neurons as the main source of new highly active neurons. Interestingly, fluctuations in neuronal activity were independent from amyloid plaque proximity, but aberrant activity levels were more likely to persist close to plaques. These results support the notion that neuronal network pathology observed in AD patients is the consequence of stable single cell aberrant neuronal activity, a finding of potential therapeutic relevance.

scholarly journals Long-term dynamics of aberrant neuronal activity in awake Alzheimer’s disease transgenic mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
V. Korzhova ◽  
P. Marinković ◽  
J. Rudan Njavro ◽  
P. M. Goltstein ◽  
F. Sun ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Neuronal Activity ◽  
Amyloid Plaque ◽  
Observation Time ◽  
Cerebral Amyloidosis ◽  
Plaque Deposition ◽  
Highly Active

AbstractAlzheimer’s disease (AD) is associated with aberrant neuronal activity, which is believed to critically determine disease symptoms. How these activity alterations emerge, how stable they are over time, and whether cellular activity dynamics are affected by the amyloid plaque pathology remains incompletely understood. We here repeatedly recorded the activity from identified neurons in cortex of awake APPPS1 transgenic mice over four weeks during the early phase of plaque deposition using in vivo two-photon calcium imaging. We found that aberrant activity during this stage largely persisted over the observation time. Novel highly active neurons slowly emerged from former intermediately active neurons. Furthermore, activity fluctuations were independent of plaque proximity, but aberrant activity was more likely to persist close to plaques. These results support the notion that neuronal network pathology observed in models of cerebral amyloidosis is the consequence of persistent single cell aberrant neuronal activity, a finding of potential diagnostic and therapeutic relevance for AD.

scholarly journals Mechanistic Aspects of Apiaceae Family Spices in Ameliorating Alzheimer’s Disease

Antioxidants ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1571
Author(s):  
Niti Sharma ◽  
Mario A. Tan ◽  
Seong Soo A. An
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Scientific Literature ◽  
Comprehensive Evaluation ◽  
Amyloid Plaque ◽  
Plaque Formation ◽  
New Strategies

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases worldwide. In an effort to search for new strategies for treating AD, natural products have become candidates of choice. Plants are a rich source of bioactive and effective compounds used in treating numerous diseases. Various plant extracts are known to display neuroprotective activities by targeting different pathophysiological pathways in association with the diseases, such as inhibiting enzymes responsible for degrading neurotransmitters, reducing oxidative stress, neuroprotection, inhibiting amyloid plaque formation, and replenishing mitochondrial function. This review presented a comprehensive evaluation of the available scientific literature (in vivo, in vitro, and in silico) on the neuroprotective mechanisms displayed by the extracts/bioactive compounds from spices belonging to the Apiaceae family in ameliorating AD.

scholarly journals Peptide Interference with APP and Tau Association: Relevance to Alzheimer’s Disease Amelioration

2020 ◽  
Vol 21 (9) ◽  
pp. 3270
Author(s):  
Ruth Maron ◽  
Gad Armony ◽  
Michael Tsoory ◽  
Meir Wilchek ◽  
Dan Frenkel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Model ◽  
Amyloid Plaque ◽  
In Vivo Studies ◽  
Nasal Administration ◽  
Plaque Burden ◽  
Cognitive Deficiency ◽  
The Brain

The two major proteins involved in Alzheimer’s disease (AD) are the amyloid precursor protein (APP) and Tau. Here, we demonstrate that these two proteins can bind to each other. Four possible peptides APP1 (390–412), APP2 (713–730), Tau1 (19–34) and Tau2 (331–348), were predicted to be involved in this interaction, with actual binding confirmed for APP1 and Tau1. In vivo studies were performed in an Alzheimer Disease animal model—APP double transgenic (Tg) 5xFAD—as well as in 5xFAD crossed with Tau transgenic 5xFADXTau (FT), which exhibit declined cognitive reduction at four months of age. Nasal administration of APP1 and Tau1 mixture, three times a week for four or five months, reduced amyloid plaque burden as well as the level of soluble Aβ 1–42 in the brain. The treatment prevented the deterioration of cognitive functions when initiated at the age of three months, before cognitive deficiency was evident, and also at the age of six months, when such deficiencies are already observed, leading to a full regain of cognitive function.

scholarly journals Modeling Aβ42 Accumulation in Response to Herpes Simplex Virus 1 Infection: 2D or 3D?

2020 ◽  
Author(s):  
Eric E. Abrahamson ◽  
Wenxiao Zheng ◽  
Vaishali Muralidaran ◽  
Milos D. Ikonomovic ◽  
David C. Bloom ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Three Dimensional ◽  
Amyloid Plaque ◽  
Neuronal Cultures ◽  
Suitable Model ◽  
Infected Cells ◽  
Hsv 1

Alzheimer's disease is a progressive neurodegenerative disease characterized neuropathologically by presence of extracellular amyloid plaques composed of fibrillar amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles. Post-mortem and in vivo studies implicate HSV-1 infection in the brain as a precipitating factor in disease/pathology initiation. HSV-1 infection of two-dimensional (2D) neuronal cultures causes intracellular accumulation of Aβ42 peptide, but these 2D models do not recapitulate the three-dimensional (3D) architecture of brain tissue. We employed human induced pluripotent stem cells (hiPSCs) to compare patterns of Aβ42 accumulation in HSV-1 infected 2D (neuronal monolayers) and 3D neuronal cultures (brain organoids). Akin to prior studies, HSV-1-infected 2D cultures showed Aβ42 immunoreactivity in cells expressing the HSV-1 antigen ICP4 (ICP4+). Conversely, accumulation of Aβ42 in ICP4+ cells in infected organoids was rarely observed. These results highlight the importance of considering 3D cultures to model host-pathogen interaction. IMPORTANCE The “pathogen” hypothesis of Alzheimer’s disease (AD) proposes that brain HSV-1 infection could be an initial source of amyloid beta (Aβ) peptide-containing amyloid plaque development. Aβ accumulation was reported in HSV-1-infected 2D neuronal cultures and neural stem cell cultures, as well as in HSV-1-infected 3D neuronal culture models. The current study extends these findings by showing different patterns of Aβ42 accumulation following HSV-1 infection of 2D compared to 3D neuronal cultures (brain organoids). Specifically, 2D neuronal cultures showed Aβ42-immunoreactivity mainly in HSV-1-infected cells and only rarely in uninfected cells or infected cells exposed to antivirals. Conversely, 3D brain organoids showed accumulation of Aβ42 mainly in non-infected cells surrounding HSV-1-infected cells. We suggest that because brain organoids better recapitulate architectural features of a developing brain than 2D cultures, they may be a more suitable model to investigate the involvement of HSV-1 in the onset of AD pathology.

Cholinesterase Inhibitors and Memantine

2008 ◽  
Author(s):  
Constantine G. Lyketsos
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholinesterase Inhibitors ◽  
Imaging Study ◽  
Behavioral Symptoms ◽  
Cognitive Symptoms ◽  
Dementia Patients ◽  
Comparison Groups

Several lines of evidence suggest that acetylcholine (ACh) neurotransmission is important to the normal functioning of memory, and loss of ACh-producing cells in the basal forebrain (nucleus basalis) is a consistent finding in patients with Alzheimer’s disease and other dementias. The most successful approach to increasing ACh in vivo has been to develop drugs that reduce its degradation by the synaptic enzyme acetylcholinesterase (AChE). Four cholinesterase inhibitors are available to treat memory and other cognitive symptoms in dementia patients. They may also stabilize or prevent the onset of milder non-cognitive neuropsychiatric or behavioral symptoms, although their use as exclusive agents for the more severe forms of the latter is not recommended. A recent Consensus Panel has articulated sound clinical principles regarding the use of these drugs in the context of the broader treatment of Alzheimer’s dementia (Lyketsos et al., 2006). Tacrine, donepezil, rivastigmine, and galantamine have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer’s disease. Tacrine should not ordinarily be used in light of the associated high risk of hepatotoxicity, its complex titration, and the availability of bettertolerated alternatives. The other three cholinesterase inhibitors seem similar in efficacy. All appear to modestly improve cognitive symptoms in 15% to 20% of patients, sometimes quite notably. In addition, they may either improve patient function and delay the emergence of behavioral symptoms or reduce the severity of the latter. The evidence does not support their use as single agents to treat more severe neuropsychiatric symptoms such as depression or delusions, although patients with apathy and visual hallucinations may respond. Any benefit of cholinesterase inhibitors to the long-term progression of dementia has not been shown conclusively. Some studies suggest that they may attenuate the long-term slope of cognitive or functional decline, but those studies have been flawed due to high levels of dropout and the use of historical untreated comparison groups. One brain imaging study, part of a clinical trial, has suggested that they may affect the size of the hippocampus or the integrity of hippocampal neurons. In the absence of replication or a better understanding of the imaging measures involved, these data are not conclusive.

IC-P-113: [18 F]BAY 94-9172 PET: Towards in vivo quantification of brain β-amyloid plaque load in Alzheimer's disease

2009 ◽  
Vol 5 (4S_Part_2) ◽  
pp. P47-P47
Author(s):  
Osama Sabri ◽  
Henryk Barthel ◽  
Georg Becker ◽  
Julia Luthardt ◽  
Marianne Patt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Plaque ◽  
Plaque Load ◽  
Β Amyloid

scholarly journals CERTL Reduces C16 Ceramide, Amyloid-β Levels and Inflammation in a Model of Alzheimer's Disease

2020 ◽  
Author(s):  
Simone Mwenda Crivelli ◽  
Qian Luo ◽  
Jo Stevens ◽  
Caterina Giovagnoni ◽  
Daan van Kruining ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Model Of Alzheimer’S Disease ◽  
Aβ Aggregation ◽  
The Brain

Abstract Background: Deregulation of ceramide and sphingomyelin levels have been suggested to contribute to the pathogenesis of Alzheimer’s disease (AD). Ceramide transfer proteins (CERTs) are ceramide carriers, crucial for ceramide and sphingomyelin balance in cells. Extracellular forms of CERTs co-localize with amyloid-β (Aβ) plaques in AD brains. To date, the significance of these observations for the pathophysiology of AD remains uncertain.Methods: The plasmid expressing CERTL, the long isoform of CERTs, was used to study the interaction of CERTL with amyloid precursor protein (APP) by co-immunoprecipitation and immunofluorescence in HEK cells. The recombinant CERTL protein was employed to study interaction of CERTL with amyloid-β (Aβ), Aβ aggregation process in presence of CERTL, and the resulting changes in Aβ toxicity in neuroblastoma cells. CERTL was overexpressed in neurons by adeno associated virus (AAV) in a familial mouse model of familial AD (5xFAD). Ten weeks after transduction animal were challenged with behavior tests for memory, anxiety and locomotion. At week twelve brains were investigated for sphingolipid levels by mass spectrometry, plaques and neuroinflammation by immunohistochemistry, gene expression and/or immunoassay.Results: Here, we report that CERTL, binds to APP, modifies Aβ aggregation and reduces Aβ neurotoxicity in vitro. Furthermore, we show that intracortical injection of AAV, mediating the expression of CERTL, decreases levels of ceramide d18:1/16:0 and increases sphingomyelin levels in the brain of male transgenic mice, modelling familial AD (5xFAD). CERTL in vivo over-expression has a mild effect on animal locomotion and decreases Aβ formation and modulates microglia by decreasing their pro-inflammatory phenotype.Conclusion: Our results demonstrate a crucial role of CERTL in regulating ceramide levels in the brain, in amyloid plaque formation and neuroinflammation, thereby opening research avenues for therapeutic targets of AD and other neurodegenerative diseases.

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