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The lysosome is responsible for protein and organelle degradation and homeostasis and the cathepsins play a key role in maintaining protein quality control. Cathepsin D (CTSD), is one such lysosomal protease, which when deficient in humans lead to neurolipofuscinosis (NCL) and is important in removing toxic protein aggregates. Prior studies demonstrated that CTSD germ-line knockout- Ctsd KO (CDKO) resulted in accumulation of protein aggregates, decreased proteasomal activities, and postnatal lethality on Day 26 ± 1. Overexpression of wildtype CTSD, but not cathepsin B, L or mutant CTSD, decreased α -synuclein toxicity in worms and mammalian cells. In this study we generated a mouse line expressing human CTSD with a floxed STOP cassette between the ubiquitous CAG promoter and the cDNA. After crossing with Nestin - cre , the STOP cassette is deleted in NESTIN + cells to allow CTSD overexpression- CTSD tg (CDtg). The CDtg mice exhibited normal behavior and similar sensitivity to sub-chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced neurodegeneration. By breeding CDtg mice with CDKO mice, we found that over-expression of CTSD extended the lifespan of the CDKO mice, partially rescued proteasomal deficits and the accumulation of A β 42 in the CDKO. This new transgenic mouse provides supports for the key role of CTSD in protecting against proteotoxicity and offers a new model to study the role of CTSD enhancement in vivo ., (© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

The etiology of late-onset Alzheimer's disease is unknown. Recent epidemiological studies suggest that exposure to high levels of ozone (O 3 ) may be a risk factor for late-onset Alzheimer's disease. Nonetheless, whether and how O 3 exposure contributes to AD development remains to be determined. In this study, we tested the hypothesis that O 3 exposure synergizes with the genetic risk factor APOE ε4 and aging leading to AD, using male apolipoprotein E (apoE)4 and apoE3 targeted replacement mice as men have increased risk exposure to high levels of O 3 via working environments and few studies have addressed APOE ε4 effects on males. Surprisingly, our results show that O 3 exposure impairs memory in old apoE3, but not old apoE4 or young apoE3 and apoE4, male mice. Further studies show that old apoE4 mice have increased hippocampal activities or expression of some enzymes involved in antioxidant defense, diminished protein oxidative modification, and neuroinflammation following O 3 exposure compared with old apoE3 mice. These novel findings highlight the complexity of interactions between APOE genotype, age, and environmental exposure in AD development., (Published by Elsevier Inc.)

The prevalence of Alzheimer's disease (AD) is higher in females than in males, and causes more severe cognitive, memory and behavioral impairments. Previously, in male transgenic (Tg) APPSweDI mice, we reported that the novel lipophilic 1,4-dihydropyridine (DHP) derivative AP-12 crossed the blood-brain barrier, blocked neuronal and vascular calcium channels, changed brain protein expression and improved behavior. In this study, we used female Tg APPSweDI mice to assess the effects of AP-12 on behavior, and brain protein expression, with a particular focus on those of the GABAergic system. The results showed that in female Tg mice, similar to male Tg mice, AP-12 improved spatial learning/memory performance in the water maze test and demonstrated anxiolytic effect in the elevated zero maze (after single administration of AP-12) and elevated plus maze (after chronic injections of AP-12). In addition, we demonstrated upregulated expression of glutamate decarboxylase 67 (GAD67) and vesicular GABA transporter (VGAT) in the cingulate cortex and hippocampus, pointing to the role of the GABAergic system as one of the neural networks dysregulated in AD. In both female and male mice, AP-12 did not change the expression of hippocampal Homer-1, a protein which is involved in synaptic plasticity. However, in cingulate cortex, the staining density of Homer-1 was significantly increased in female mice. Further, female mice (similar to male mice) did not show changes in brain AChE expression and in the amyloid beta load in the hippocampus and cingulate cortex. In conclusion, the memory enhancing, anxiolytic and protein expression effects of AP-12 did not show sex specificity in APPSweDI mice. Considering the ability of AP-12 to block brain calcium channels and improve memory by enhancing the GABAergic and synaptic plasticity processes, AP-12 is a promising compound which merits further pre-clinical studies to investigate its usefulness in the treatment of AD., Competing Interests: statement None declared., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

One of the two characteristic pathological hallmarks of Alzheimer's disease (AD) are neuritic plaques. The sequence of events leading to the extracellular deposition of amyloid β (Aβ) peptides in plaques or in diffuse deposits is not clear. Here we investigate the relationship between aggregation and deposition of Aβ by using peptides that bind to Aβ as antifibrillization treatments in APP/PS1 double transgenic AD-model mice. Using Alzet minipumps, we infused the brain of these AD-model mice for 4 weeks with one of the three small D-amino acid peptides (i.e., D1, D3, or D3-FITC) that were designed to bind specifically to Aβ42, and examined the subsequent improvement in cognitive deficits after 3 weeks and analyzed amyloid deposition in the brain following the behavioral analysis. Cognitive deficits are similar comparing control and D3-treated mice, but D1-treated mice are slightly, but significantly, impaired. In contrast, there is a substantial improvement in the cognitive deficits in the animals treated with D3-FITC, compared to the other mice. In contrast, we show that there is a substantial reduction in the amount of amyloid deposits in the animals treated with D3, compared to the other groups of mice. Furthermore, the amount of activated microglia and astrocytes surrounding Aβ deposits is dramatically reduced in both the D3- and D3-FITC-treated mice. Our findings demonstrate that treatments with a high-affinity Aβ-42-binding D-amino acid peptide significantly decrease Aβ deposits and the associated inflammatory response. Together, this suggests that aggregation likely plays an important role in the deposition of Aβ protein in APP/PS1 transgenic mice and that antiaggregation treatments with D-peptides may be successful in AD patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We have established a novel transgenic rat line carrying human microtubule-associated protein Tau-40 with mutation P301L. hTau-40/P301L transgenic male and female rats were followed up to 2 years of age. The hTau-40/P301L rats expressed human tau mRNA and protein in the limbic cortex and associated white matter, hippocampus and spinal cord. With increasing age, the staining density for phosphorylated tau increased in all these areas. Neither silver stains nor Fluoro-Jade staining indicated the presence of dying neurons, or axonal degeneration, and there was no evidence of increased gliosis or inflammation. However, some neurons did display dendritic abnormalities, and immunoblots revealed the presence of sarcosyl insoluble tau. A large test battery revealed no behavioral abnormalities in these rats, except a mild hyperactivity in the elevated plus maze. In conclusion, this transgenic tau rat may be a useful model for 'pretangle' pathology, although in this study conditions were not sufficient to induce significant neuronal loss or behavioral deficits., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Recently it has been shown that over 3-year-old wild-type South American rodents, Octodon degus, the "common degu" or degu, of their own accord develop Alzheimer's disease neuropathological hallmarks: amyloid-β-peptide depositions and accumulation of tau-protein. Here we analyzed brains of 1-, 3- and 6-year-old degu's, bred in standard animal facilities. Significant amounts of Aβ and tau deposits are present in the hippocampal formation of 6-year-old O. degus, primarily in the white matter, but these hippocampal Aβ and tau deposits are not present in younger ones. In contrast, significant Aβ deposits in blood vessel walls are already found in 3-year-old animals. The tau deposits in the hippocampal formation coincide with a significant decrease in staining for myelin in the same areas, indicating hippocampal disconnection and, likely, dysfunction. Our findings indicate that (1) cerebral amyloid angiopathy precedes brain parenchyma pathology in aged degu's and (2) the onset of disease seems to be delayed in the laboratory vs. wild-type degu's., (Copyright © 2009 Elsevier Inc. All rights reserved.)

Accumulation of amyloid beta peptide (Aβ) in the brain is a pathological hallmark of Alzheimer's disease (AD); the underlying mechanism, however, is not well understood. In this study, we show that expression of plasminogen activator inhibitor 1 (PAI-1), a physiological inhibitor of tissue type and urokinase type plasminogen activators (tPA and uPA), increases with age in the brain of wild type and Aβ precursor protein-presenilin 1 (APP/PS1) transgenic mice as well as in AD patients. Most importantly, we show that knocking out the PAI-1 gene dramatically reduces Aβ burden in the brain of APP/PS1 mice but has no effect on the levels of full-length APP, alpha or beta C-terminal fragments. Furthermore, we show that knocking out the PAI-1 gene leads to increases in the activities of tPA and plasmin, and the plasmin activity inversely correlates with the amounts of SDS insoluble Aβ40 and Aβ42. Together, these data suggest that increased PAI-1 expression/activity contributes importantly to Aβ accumulation during aging and in AD probably by inhibiting plasminogen activation and thus Aβ degradation., (Copyright © 2009 Elsevier Inc. All rights reserved.)

Learning and memory are two of the fundamental cognitive functions that confer us the ability to accumulate knowledge from our experiences. Although we use these two mental skills continuously, understanding the molecular basis of learning and memory is very challenging. Methylation modification of DNA is an epigenetic mechanism that plays important roles in regulating gene expression, which is one of the key processes underlying the functions of cells including neurons. Interestingly, a genome-wide decline in DNA methylation occurs in the brain during normal aging, which coincides with a functional decline in learning and memory with age. It has been speculated that DNA methylation in neurons might be involved in memory coding. However, direct evidence supporting the role of DNA methylation in memory formation is still under investigation. This particular function of DNA methylation has not drawn wide attention despite several important studies that have provided supportive evidence for the epigenetic control of memory formation. To facilitate further exploration of the epigenetic basis of memory function, we will review existing studies on DNA methylation that are related to the development and function of the nervous system. We will focus on studies illustrating how DNA methylation regulates neural activities and memory formation via the control of gene expression in neurons, and relate these studies to various age-related neurological disorders that affect cognitive functions.

The inflammatory cytokines can initiate nerve cell degeneration and enhance the plaque production typically found in Alzheimer's disease (AD). Interleukin-18 (IL-18) is an inflammatory cytokine, which can induce the expression of interferon-gamma. This interleukin shares similarities with the IL-1 family of proteins. Like IL-1 beta, IL-18 is cleaved by caspase-1 (ICE) to an active secreted form. We examined the expressions of IL-18, -1 beta and ICE in different brain regions from AD patients that were categorized with respect to the Braak stage, and age-matched with non-demented controls. The levels of total-RNA and protein of IL-18 and ICE were increased, especially in the frontal lobe of AD patients and this change was not modified by ApoE genotype. Immunohistochemistry of AD brain samples detected IL-18 in microglia, astrocytes, and surprisingly in neurons, and it is also co-localized not only with amyloid-beta plaques but also with tau. In CSF, elevated IL-18 level was detected only in men and it also correlated with CSF tau in MCI. IL-18 may thus be a potential biomarker for men. Plasma levels of IL-18 showed no correlation with the disease. In conclusion, amyloid-beta may induce the synthesis of IL-18, and IL-18 kinases involved in tau phosphorylation as a part of the amyloid-associated inflammatory reaction.

Background: The mammalian forkhead box, class O (FoxO) transcription factors function to regulate diverse physiological processes. Emerging evidence that both brain-derived neurotrophic factor (BDNF) and lithium suppress FoxO activity suggests a potential role of FoxOs in regulating mood-relevant behavior. Here, we investigated whether brain FoxO1 and FoxO3a can be regulated by serotonin and antidepressant treatment and whether their genetic deletion affects behaviors., Methods: C57BL/6 mice were treated with D-fenfluramine to increase brain serotonergic activity or with the antidepressant imipramine. The functional status of brain FoxO1 and FoxO3a was audited by immunoblot analysis for phosphorylation and subcellular localization. The behavioral manifestations in FoxO1- and FoxO3a-deficient mice were assessed via the Elevated Plus Maze Test, Forced Swim Test, Tail Suspension Test, and Open Field Test., Results: Increasing serotonergic activity by d-fenfluramine strongly increased phosphorylation of FoxO1 and FoxO3a in several brain regions and reduced nuclear FoxO1 and FoxO3a. The effect of D-fenfluramine was mediated by the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Chronic, but not acute, treatment with the antidepressant imipramine also increased the phosphorylation of brain FoxO1 and FoxO3a. When FoxO1 was selectively deleted from brain, mice displayed reduced anxiety. In contrast, FoxO3a-deficient mice presented with a significant antidepressant-like behavior., Conclusions: FoxOs may be a transcriptional target for anxiety and mood disorder treatment. Despite their physical and functional relatedness, FoxO1 and FoxO3a influence distinct behavioral processes linked to anxiety and depression. Findings in this study reveal important new roles of FoxOs in brain and provide a molecular framework for further investigation of how FoxOs may govern mood and anxiety disorders.

Rats display an age-related impairment in learning and memory; however, few studies have systematically examined this relationship in multiple strains. The present study used a repeated acquisition water maze task to test the hypothesis that age-related decreases in learning and memory occur at different rates in three strains of rats, i.e. Sprague-Dawley (SD), spontaneously hypertensive (SHR), and Wistar Kyoto (WKY) rats. All three strains of rats displayed age-related decreases in spatial learning and memory; however, the rate of decline differed between the strains. Compared to young rats of the same strain, only SHR were significantly impaired at 12 months of age. All three strains displayed moderate impairment in learning the task at 18 months of age, and at 24 months of age all three strains of rats were severely impaired in the task, but SD performed best at 18 and 24 months of age. Further, SD and SHR displayed a probe trial bias at 3 months of age, but only SD had a bias at 12 months of age and none of the rats showed the bias at later ages. Thus, in these three strains, age-related impairment of spatial memory proceeds at different rates.