Spermine protects aluminium chloride and iron-induced neurotoxicity in rat model of Alzheimer's disease via attenuation of tau phosphorylation, Amyloid-β (1–42) and NF-κB pathway

Neuroinflammation driven by the accumulation of amyloid β (Aβ) can lead to neurofibrillary tangle formation in Alzheimer’s Disease (AD). To test the hypothesis that an anti-inflammatory immunomodulatory agent might have beneficial effects on amyloid and tau pathology, as well as microglial phenotype, we evaluated glatiramer acetate (GA), a multiple sclerosis drug thought to bias type 2 helper T (Th2) cell responses and alternatively activate myeloid cells. We administered weekly subcutaneous injections of GA or PBS to 15-month-old 3xTg AD mice, which develop both amyloid and tau pathology, for a period of 8 weeks. We found that subcutaneous administration of GA improved behavioral performance in novel object recognition and decreased Aβ plaque in the 3xTg AD mice. Changes in tau phosphorylation were mixed with specific changes in phosphoepitopes seen in immunohistochemistry but not observed in western blot. In addition, we found that there was a trend toward increased microglia complexity in 3xTg mice treated with GA, suggesting a shift toward homeostasis. These findings correlated with subtle changes in the microglial transcriptome, in which the most striking difference was the upregulation of Dcstamp. Lastly, we found no evidence of changes in proportions of major helper T cell (Th) subtypes in the periphery. Overall, our study provides further evidence for the benefits of immunomodulatory therapies that alter the adaptive immune system with the goal of modifying microglia responses for the treatment of Alzheimer’s Disease.

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Therapeutic effect of Melissa officinalis in an amyloid-β rat model of Alzheimer’s disease

Journal of Herbmed Pharmacology ◽

10.15171/jhp.2018.31 ◽

2018 ◽

Vol 7 (3) ◽

pp. 193-199 ◽

Cited By ~ 1

Author(s):

Siamak Beheshti ◽

Bahareh Shahmoradi

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Effect ◽

Rat Model ◽

Amyloid Β ◽

Melissa Officinalis ◽

Model Of Alzheimer’S Disease

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Neuronal and Astrocytic Metabolism in a Transgenic Rat Model of Alzheimer's Disease

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2014.37 ◽

2014 ◽

Vol 34 (5) ◽

pp. 906-914 ◽

Cited By ~ 41

Author(s):

Linn Hege Nilsen ◽

Menno P Witter ◽

Ursula Sonnewald

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Frontal Cortex ◽

Rat Model ◽

Hippocampal Formation ◽

Tricarboxylic Acid Cycle ◽

Amyloid Β ◽

Transgenic Rat ◽

Resonance Spectroscopy ◽

Model Of Alzheimer’S Disease

Regional hypometabolism of glucose in the brain is a hallmark of Alzheimer's disease (AD). However, little is known about the specific alterations of neuronal and astrocytic metabolism involved in homeostasis of glutamate and GABA in AD. Here, we investigated the effects of amyloid β (Aβ) pathology on neuronal and astrocytic metabolism and glial-neuronal interactions in amino acid neurotransmitter homeostasis in the transgenic McGill-R-Thyl-APP rat model of AD compared with healthy controls at age 15 months. Rats were injected with [1-13C]glucose and [1,2-13C]acetate, and extracts of the hippocampal formation as well as several cortical regions were analyzed using 1H- and 13C nuclear magnetic resonance spectroscopy and high-performance liquid chromatography. Reduced tricarboxylic acid cycle turnover was evident for glutamatergic and GABAergic neurons in hippocampal formation and frontal cortex, and for astrocytes in frontal cortex. Pyruvate carboxylation, which is necessary for de novo synthesis of amino acids, was decreased and affected the level of glutamine in hippocampal formation and those of glutamate, glutamine, GABA, and aspartate in the retrosplenial/cingulate cortex. Metabolic alterations were also detected in the entorhinal cortex. Overall, perturbations in energy- and neurotransmitter homeostasis, mitochondrial astrocytic and neuronal metabolism, and aspects of the glutamate-glutamine cycle were found in McGill-R-Thy1-APP rats.

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Characterization of a Mouse Model of Alzheimer’s Disease Expressing Aβ4-42 and Human Mutant Tau

International Journal of Molecular Sciences ◽

10.3390/ijms22105191 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5191

Author(s):

Silvia Zampar ◽

Oliver Wirths

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Pyramidal Neurons ◽

Behavioral Assessment ◽

Large Body ◽

Amyloid Β ◽

Tau Phosphorylation ◽

Model Of Alzheimer’S Disease

The relationship between the two most prominent neuropathological hallmarks of Alzheimer’s Disease (AD), extracellular amyloid-β (Aβ) deposits and intracellular accumulation of hyperphosphorylated tau in neurofibrillary tangles (NFT), remains at present not fully understood. A large body of evidence places Aβ upstream in the cascade of pathological events, triggering NFTs formation and the subsequent neuron loss. Extracellular Aβ deposits were indeed causative of an increased tau phosphorylation and accumulation in several transgenic models but the contribution of soluble Aβ peptides is still controversial. Among the different Aβ variants, the N-terminally truncated peptide Aβ4–42 is among the most abundant. To understand whether soluble Aβ4–42 peptides impact the onset or extent of tau pathology, we have crossed the homozygous Tg4–42 mouse model of AD, exclusively expressing Aβ4–42 peptides, with the PS19 (P301S) tau transgenic model. Behavioral assessment showed that the resulting double-transgenic line presented a partial worsening of motor performance and spatial memory deficits in the aged group. While an increased loss of distal CA1 pyramidal neurons was detected in young mice, no significant alterations in hippocampal tau phosphorylation were observed in immunohistochemical analyses.

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