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 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 Alternative Treatment for Alzheimer’s Disease: Porphyromonas gingivalis Inhibitors

2019 ◽  
pp. 23-25
Author(s):  
Pouriya Sadeghighazichaki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Porphyromonas Gingivalis ◽  
Virulence Factor ◽  
Bacterial Load ◽  
Amyloid Plaque ◽  
Plaque Deposition ◽  
The Brain

Porphyromonas gingivalis (P. gingivalis), has been identified as a primary pathogen in causing chronic periodontitis, or gum inflammation. P. gingivalis was also isolated in brain samples of patients suffering from Alzheimer’s disease. A virulence factor of P. gingivalis called gingipains, releases proteases responsible for neurodegeneration and has been identified in the brain of patients suffering from Alzheimer’s. Studies show that mice infected with P. gingivalis demonstrate an increase in amyloid plaque deposition in brain samples. Further investigation identified gingipains as a neurotoxic agent, both in vivo and in vitro, which impacts the structure of tau protein, responsible for the normal functioning of neurons. Small-molecule inhibitors targeting gingipains are utilized to prevent the neurotoxic effects of gingipains and facilitate neuronal regeneration. Inhibition of this virulence factor reduced the overall bacterial load, blocked amyloid-beta production, prevented neuroinflammation, and allowed for neuronal recovery. These findings provide a new outlook for the onset of Alzheimer’s disease and elucidate a much-needed potential treatment for the condition.

scholarly journals α-1-Antichymotrypsin Promotes β-Sheet Amyloid Plaque Deposition in a Transgenic Mouse Model of Alzheimer's Disease

2001 ◽  
Vol 21 (5) ◽  
pp. 1444-1451 ◽  
Author(s):  
Lars N. G. Nilsson ◽  
Kelly R. Bales ◽  
Giovanni DiCarlo ◽  
Marcia N. Gordon ◽  
Dave Morgan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Amyloid Plaque ◽  
Transgenic Mouse Model ◽  
Plaque Deposition ◽  
Model Of Alzheimer’S Disease ◽  
Β Sheet

scholarly journals N,N′-Diacetyl-p-phenylenediamine restores microglial phagocytosis and improves cognitive defects in Alzheimer’s disease transgenic mice

2019 ◽  
Vol 116 (47) ◽  
pp. 23426-23436 ◽  
Author(s):  
Min Hee Park ◽  
Misun Lee ◽  
Geewoo Nam ◽  
Mingeun Kim ◽  
Juhye Kang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Amyloid Β ◽  
Causative Factor ◽  
Central Feature ◽  
Microglial Phagocytosis ◽  
Cognitive Defects

As a central feature of neuroinflammation, microglial dysfunction has been increasingly considered a causative factor of neurodegeneration implicating an intertwined pathology with amyloidogenic proteins. Herein, we report the smallest synthetic molecule (N,N′-diacetyl-p-phenylenediamine [DAPPD]), simply composed of a benzene ring with 2 acetamide groups at the para position, known to date as a chemical reagent that is able to promote the phagocytic aptitude of microglia and subsequently ameliorate cognitive defects. Based on our mechanistic investigations in vitro and in vivo, 1) the capability of DAPPD to restore microglial phagocytosis is responsible for diminishing the accumulation of amyloid-β (Aβ) species and significantly improving cognitive function in the brains of 2 types of Alzheimer’s disease (AD) transgenic mice, and 2) the rectification of microglial function by DAPPD is a result of its ability to suppress the expression of NLRP3 inflammasome-associated proteins through its impact on the NF-κB pathway. Overall, our in vitro and in vivo investigations on efficacies and molecular-level mechanisms demonstrate the ability of DAPPD to regulate microglial function, suppress neuroinflammation, foster cerebral Aβ clearance, and attenuate cognitive deficits in AD transgenic mouse models. Discovery of such antineuroinflammatory compounds signifies the potential in discovering effective therapeutic molecules against AD-associated neurodegeneration.

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.

Anti-diabetic vanadyl complexes reduced Alzheimer’s disease pathology independent of amyloid plaque deposition

2018 ◽  
Vol 62 (1) ◽  
pp. 126-139 ◽  
Author(s):  
Yaqiong Dong ◽  
Tessandra Stewart ◽  
Yue Zhang ◽  
Min Shi ◽  
Chang Tan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Plaque ◽  
Plaque Deposition ◽  
Vanadyl Complexes
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