scholarly journals From reaction kinetics to dementia: A simple dimer model of Alzheimer’s disease etiology

2021 ◽  
Vol 17 (7) ◽  
pp. e1009114
Author(s):  
Michael R. Lindstrom ◽  
Manuel B. Chavez ◽  
Elijah A. Gross-Sable ◽  
Eric Y. Hayden ◽  
David B. Teplow
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Degeneration ◽  
Theoretical Calculations ◽  
Disease Incidence ◽  
Current Model ◽  
Protein A ◽  
Science Data ◽  
Disease Etiology ◽  
Model Of Alzheimer’S Disease

Oligomers of the amyloid β-protein (Aβ) have been implicated in the pathogenesis of Alzheimer’s disease (AD) through their toxicity towards neurons. Understanding the process of oligomerization may contribute to the development of therapeutic agents, but this has been difficult due to the complexity of oligomerization and the metastability of the oligomers thus formed. To understand the kinetics of oligomer formation, and how that relates to the progression of AD, we developed models of the oligomerization process. Here, we use experimental data from cell viability assays and proxies for rate constants involved in monomer-dimer-trimer kinetics to develop a simple mathematical model linking Aβ assembly to oligomer-induced neuronal degeneration. This model recapitulates the rapid growth of disease incidence with age. It does so through incorporation of age-dependent changes in rates of Aβ monomer production and elimination. The model also describes clinical progression in genetic forms of AD (e.g., Down’s syndrome), changes in hippocampal volume, AD risk after traumatic brain injury, and spatial spreading of the disease due to foci in which Aβ production is elevated. Continued incorporation of clinical and basic science data into the current model will make it an increasingly relevant model system for doing theoretical calculations that are not feasible in biological systems. In addition, terms in the model that have particularly large effects are likely to be especially useful therapeutic targets.

scholarly journals N-Acetyl Cysteine Supplement Minimize Tau Expression and Neuronal Loss in Animal Model of Alzheimer’s Disease

2018 ◽  
Vol 8 (10) ◽  
pp. 185 ◽  
Author(s):  
Teresa Joy ◽  
Muddanna Rao ◽  
Sampath Madhyastha
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Model ◽  
Neuronal Degeneration ◽  
Neuronal Loss ◽  
Model Of Alzheimer’S Disease ◽  
Acetyl Cysteine ◽  
The Brain ◽  
Tau Expression

Alzheimer’s disease (AD) is characterized by the accumulation of neurofibrillary tangles (NFT), deposition of beta amyloid plaques, and consequent neuronal loss in the brain tissue. Oxidative stress to the neurons is often attributed to AD, but its link to NFT and β-amyloid protein (BAP) still remains unclear. In an animal model of AD, we boosted the oxidative defense by N-Acetyl cysteine (NAC), a precursor of glutathione, a powerful antioxidant and free radical scavenger, to understand the link between oxidative stress and NFT. In mimicking AD, intracerebroventricular (ICV) colchicine, a microtubule disrupting agent also known to cause oxidative stress was administered to the rats. The animal groups consisted of an age-matched control, sham operated, AD, and NAC treated in AD models of rats. Cognitive function was evaluated in a passive avoidance test; neuronal degeneration was quantified using Nissl staining. NFT in the form of abnormal tau expression in different regions of the brain were evaluated through immunohistochemistry using rabbit anti-tau antibody. ICV has resulted in significant cognitive and neuronal loss in medial prefrontal cortex (MFC) and all the regions of the hippocampus. It has also resulted in increased accumulation of intraneuronal tau in the hippocampus and MFC. NAC treatment in AD model rats has reversed the cognitive loss and neuronal degeneration. The intraneuronal tau expression also minimized with NAC treatment in AD model rats. Thus, our findings suggest that an antioxidant supplement during the progression of AD is likely to prevent neuronal degeneration by minimizing the neurofibrillary degeneration in the form of tau accumulation.

scholarly journals The effect of PN-1, a Traditional Chinese Prescription, on the Learning and Memory in a Transgenic Mouse Model of Alzheimer’s Disease

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Zhi-Gang Yao ◽  
Ling Zhang ◽  
Liang Liang ◽  
Yu Liu ◽  
Ya-Jun Yang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Learning And Memory ◽  
Protein A ◽  
Transgenic Animals ◽  
Plaque Burden ◽  
Intragastric Administration ◽  
Amyloid Beta Protein ◽  
Promising Alternative ◽  
Model Of Alzheimer’S Disease

Traditional Chinese Medicine (TCM) is a complete medical system that has been practiced for more than 3000 years. Prescription number 1 (PN-1) consists of several Chinese medicines and is designed according to TCM theories to treat patients with neuropsychiatric disorders. The evidence of clinical practice suggests the benefit effects of PN-1 on cognitive deficits of dementia patients. We try to prove and explain this by using contemporary methodology and transgenic animal models of Alzheimer’s disease (AD). The behavioral studies were developed to evaluate the memory of transgenic animals after intragastric administration of PN-1 for 3 months. Amyloid beta-protein (Aβ) neuropathology was quantified using immunohistochemistry and ELISA. The western blotting was used to detect the levels of plasticity associated proteins. The safety of PN-1 on mice was also assessed through multiple parameters. Results showed that PN-1 could effectively relieve learning and memory impairment of transgenic animals. Possible mechanisms showed that PN-1 could significantly reduce plaque burden and Aβlevels and boost synaptic plasticity. Our observations showed that PN-1 could improve learning and memory ability through multiple mechanisms without detectable side effects on mice. We propose that PN-1 is a promising alternative treatment for AD in the future.

scholarly journals Loss of Hippocampal Calretinin and Parvalbumin Interneurons in the 5XFAD Mouse Model of Alzheimer’s Disease

ASN NEURO ◽  
2020 ◽  
Vol 12 ◽  
pp. 175909142092535 ◽  
Author(s):  
Naomi K. Giesers ◽  
Oliver Wirths
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Calcium Binding ◽  
Neuronal Degeneration ◽  
Disease Process ◽  
Amyloid Β ◽  
Gamma Aminobutyric Acid ◽  
Wild Type ◽  
Model Of Alzheimer’S Disease

The deposition of amyloid-β peptides in the form of extracellular plaques and neuronal degeneration belong to the hallmark features of Alzheimer’s disease (AD). In addition, impaired calcium homeostasis and altered levels in calcium-binding proteins seem to be associated with the disease process. In this study, calretinin- (CR) and parvalbumin- (PV) positive gamma-aminobutyric acid-producing (GABAergic) interneurons were quantified in different hippocampal subfields of 12-month-old wild-type mice, as well as in the transgenic AD mouse models 5XFAD and Tg4-42. While, in comparison with wild-type mice, CR-positive interneurons were mainly reduced in the CA1 and CA2/3 regions in plaque-bearing 5XFAD mice, PV-positive interneurons were reduced in all analyzed subfields including the dentate gyrus. No reduction in CR- and PV-positive interneuron numbers was detected in the non-plaque-forming Tg4-42 mouse, although this model has been previously demonstrated to harbor a massive loss of CA1 pyramidal neurons. These results provide information about hippocampal interneuron numbers in two relevant AD mouse models, suggesting that interneuron loss in this brain region may be related to extracellular amyloid burden.

Proteolytic processing of the amyloid-beta protein precursor of Alzheimer's disease

2002 ◽  
Vol 38 ◽  
pp. 37-49 ◽  
Author(s):  
Janelle Nunan ◽  
David H Small
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Alternative Pathway ◽  
Protein A ◽  
Proteolytic Processing ◽  
Gamma Secretase ◽  
Amyloid Beta Protein ◽  
Protein Precursor ◽  
Amyloid Beta Protein Precursor

The proteolytic processing of the amyloid-beta protein precursor plays a key role in the development of Alzheimer's disease. Cleavage of the amyloid-beta protein precursor may occur via two pathways, both of which involve the action of proteases called secretases. One pathway, involving beta- and gamma-secretase, liberates amyloid-beta protein, a protein associated with the neurodegeneration seen in Alzheimer's disease. The alternative pathway, involving alpha-secretase, precludes amyloid-beta protein formation. In this review, we describe the progress that has been made in identifying the secretases and their potential as therapeutic targets in the treatment or prevention of Alzheimer's disease.

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