Inhee Mook-Jung

Dynamics of Population Code for Working Memory in the Prefrontal Cortex

Some neurons (delay cells) in the prefrontal cortex elevate their activities throughout the time period during which the animal is required to remember past events and prepare future behavior, suggesting that working memory is mediated by continuous neural activity. It is unknown, however, how working memory is represented within a population of prefrontal cortical neurons. We recorded from neuronal ensembles in the prefrontal cortex as rats learned a new delayed alternation task. Ensemble activities changed in parallel with behavioral learning so that they increasingly allowed correct decoding of previous and future goal choices. In well-trained rats, considerable decoding was possible based on only a few neurons and after removing continuously active delay cells. These results show that neural activity in the prefrontal cortex changes dynamically during new task learning so that working memory is robustly represented and that working memory can be mediated by sequential activation of different neural populations.

Ginsenoside Rb1 and Rg1 Improve Spatial Learning and Increase Hippocampal Synaptophysin Level in Mice

We investigated the cognition enhancing effects of ginsenoside Rb1 and Rg1. Mice were trained in a Morris water maze following injection (i.p.) of Rb1 (1 mg/kg) or Rg1 (1 mg/kg) for 4 days. Both Rb1‐ and Rg1‐injected mice showed enhanced spatial learning compared to control animals. The hippocampus, but not the frontal cortex, of treated mice contained higher density of a synaptic marker protein, synaptophysin, compared to control mice. Electrophysiological recordings in hippocampal slices revealed that Rb1 or Rg1 injection did not change the magnitude of paired‐pulse facilitation or long‐term potentiation. Our results suggest that Rb1 and Rg1 enhance spatial learning ability by increasing hippocampal synaptic density without changing plasticity of individual synapses. J. Neurosci. Res. 63:509–515, 2001.

Lovastatin enhances Aβ production and senile plaque deposition in female Tg2576 mice

A recent clinical study showed that statins, which are inhibitors of cholesterol biosynthesis pathway, reduced the prevalence of Alzheimers disease (AD). Animal studies that have employed high cholesterol diet indicate significant relationship between cholesterol level and senile plaque deposition. Here, we investigated the effects of lovastatin on beta-amyloid production and senile plaque deposition in an animal model of AD (Tg2576 mice). As expected, lovastatin treatment reduced plasma cholesterol level in both male and female mice. However, lovastatin enhanced the amounts of beta-amyloid and other beta-secretase derived peptides in females, but not in males. Likewise, lovastatin increased the number of plaques in the hippocampus and cortex of females, but not in males. Lovastatin did not change the amounts of full-length or alpha-secretase processed amyloid precursor protein (APP), or presenilin 1 (PS1) in either sex. Thus, lovastatin lowers cholesterol level in both genders, but enhances beta-amyloid production and senile plaque deposition only in brains of female Tg2576 mice. Our results suggest that low plasma cholesterol levels might be a risk factor for AD in females.

Amyloid peptide attenuates the proteasome activity in neuronal cells

Previous studies have suggested a possible relationship between the ubiquitin-proteasome pathway and some pathological manifestations of Alzheimers disease (AD). This study investigated the possibility that the Abeta peptides interact with the ubiquitin-proteasome pathway inside neuronal cells. The ubiquitin-proteasome activity decreased with age in the brains of Tg2576 mice while the Abeta(1-42) levels increased. In cultured neuronal cells, an extracellular treatment of Abeta markedly decreased the proteasome activity and extracellular treated Abeta peptides were found in the cytoplasmic compartment. These results suggest that the extracellular Abeta peptides enter the cell and inhibit the proteasome activity, which might play a role in the pathogenesis of AD.

Protective effects of asiaticoside derivatives against beta-amyloid neurotoxicity.

Asiaticoside (AS) derivatives were tested for potential protective effects against Aβ‐induced cell death. Of the 28 AS derivatives tested, asiatic acid (AA), asiaticoside 6 (AS6), and SM2 showed strong inhibition of Aβ‐induced death of B103 cells at 1 μM. The three AS derivatives were further tested for their effects on free radical injury and apoptosis. All three AS derivatives reduced H2O2‐induced cell death and lowered intracellular free radical concentration, but AA showed the strongest protection. In contrast, SM2 was the most effective blocker of staurosporine‐induced apoptosis. These results suggest that the three AS derivatives block Aβ toxicity by acting through different cellular mechanisms. When applied to hippocampal slices, AA, SM2, and AS6 did not alter n‐methyl‐D‐aspartic acid (NMDA) or non‐NMDA receptor‐mediated synaptic transmission, paired‐pulse facilitation or induction of long‐term potentiation in the field CA1. These results indicate that the three AS derivatives do not alter physiological properties of the hippocampus at the concentration that blocks Aβ‐induced cell death. Therefore AS6, AA, and SM2 can be regarded as reasonable candidates for a therapeutic Alzheimers disease drug that protects neurons from Aβ toxicity. J. Neurosci. Res. 58:417–425, 1999.

Aβ1–42-RAGE Interaction Disrupts Tight Junctions of the Blood–Brain Barrier Via Ca2+-Calcineurin Signaling

The blood–brain barrier (BBB), which is formed by adherens and tight junctions (TJs) of endothelial cells, maintains homeostasis of the brain. Disrupted intracellular Ca2+ homeostasis and breakdown of the BBB have been implicated in the pathogenesis of Alzheimers disease (AD). The receptor for advanced glycation end products (RAGE) is known to interact with amyloid β-peptide (Aβ) and mediate Aβ transport across the BBB, contributing to the deposition of Aβ in the brain. However, molecular mechanisms underlying Aβ-RAGE interaction-induced alterations in the BBB have not been identified. We found that Aβ1–42 induces enhanced permeability, disruption of zonula occludin-1 (ZO-1) expression in the plasma membrane, and increased intracellular calcium and matrix metalloproteinase (MMP) secretion in cultured endothelial cells. Neutralizing antibodies against RAGE and inhibitors of calcineurin and MMPs prevented Aβ1–42-induced changes in ZO-1, suggesting that Aβ-RAGE interactions alter TJ proteins through the Ca2+-calcineurin pathway. Consistent with these in vitro findings, we found disrupted microvessels near Aβ plaque-deposited areas, elevated RAGE expression, and enhanced MMP secretion in microvessels of the brains of 5XFAD mice, an animal model for AD. We have identified a potential molecular pathway underlying Aβ-RAGE interaction-induced breakage of BBB integrity. This pathway might play an important role in the pathogenesis of AD.

Mitochondria-Specific Accumulation of Amyloid β Induces Mitochondrial Dysfunction Leading to Apoptotic Cell Death

Mitochondria are best known as the essential intracellular organelles that host the homeostasis required for cellular survival, but they also have relevance in diverse disease-related conditions, including Alzheimers disease (AD). Amyloid β (Aβ) peptide is the key molecule in AD pathogenesis, and has been highlighted in the implication of mitochondrial abnormality during the disease progress. Neuronal exposure to Aβ impairs mitochondrial dynamics and function. Furthermore, mitochondrial Aβ accumulation has been detected in the AD brain. However, the underlying mechanism of how Aβ affects mitochondrial function remains uncertain, and it is questionable whether mitochondrial Aβ accumulation followed by mitochondrial dysfunction leads directly to neuronal toxicity. This study demonstrated that an exogenous Aβ1–42 treatment, when applied to the hippocampal cell line of mice (specifically HT22 cells), caused a deleterious alteration in mitochondria in both morphology and function. A clathrin-mediated endocytosis blocker rescued the exogenous Aβ1–42-mediated mitochondrial dysfunction. Furthermore, the mitochondria-targeted accumulation of Aβ1–42 in HT22 cells using Aβ1–42 with a mitochondria-targeting sequence induced the identical morphological alteration of mitochondria as that observed in the APP/PS AD mouse model and exogenous Aβ1–42-treated HT22 cells. In addition, subsequent mitochondrial dysfunctions were demonstrated in the mitochondria-specific Aβ1–42 accumulation model, which proved indistinguishable from the mitochondrial impairment induced by exogenous Aβ1–42-treated HT22 cells. Finally, cellular toxicity was directly induced by mitochondria-targeted Aβ1–42 accumulation, which mimics the apoptosis process in exogenous Aβ1–42-treated HT22 cells. Taken together, these results indicate that mitochondria-targeted Aβ1–42 accumulation is the necessary and sufficient condition for Aβ-mediated mitochondria impairments, and leads directly to cellular death rather than along with other Aβ-mediated signaling alterations.

Neuroprotective effect of genistein against beta amyloid-induced neurotoxicity.

Estrogen is beneficial to patients with Alzheimers disease (AD) but has a limited clinical use due to its proliferative and oncogenic effects on non-neuronal cells responsive to estrogen. In an attempt to find an estrogen substitute that retains the beneficial effects of estrogen with minimal side effects, we compared the neuroprotective and proliferative effects of genistein, a selective estrogen receptor (ER) beta-agonist, with those of estrogen. Genistein and 17beta-estradiol showed comparable levels of protection against Abeta-induced deaths of cultured SH-SY5Y human neuroblastoma cells, which were blocked by an estrogen receptor antagonist, ICI 182,780. On the other hand, 17beta-estradiol, but not genistein, induced proliferation of uterine endometrial cells. Our results suggest that genistein is a potential alternative to estrogen in the treatment of Alzheimers disease.

SORL1 Is Genetically Associated with Late-Onset Alzheimer’s Disease in Japanese, Koreans and Caucasians

To discover susceptibility genes of late-onset Alzheimer’s disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values <2×10−5 were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P = 7.33×10−7 in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P = 1.77×10−9) and rs3781834 (P = 1.04×10−8). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P = 1.71×10−5) and rs744373 near BIN1 (P = 1.39×10−4). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations.

RAGE regulates BACE1 and Aβ generation via NFAT1 activation in Alzheimer’s disease animal model

The receptor for advanced glycation end products (RAGE) is a multiligand cell surface receptor, and amyloid P peptide (Aβ) is one of the ligands for RAGE. Because RAGE is a transporter of Aβ from the blood to the brain, RAGE is believed to play an important role in Alzheimers disease (AD) pathogenesis. In the present study, the role of RAGE in Aβ production was examined in the brain tissue of an AD animal model, Tg2576 mice, as well as cultured cells. Because β‐site APP‐cleaving enzyme 1 (BACE1), an essential protease for Aβ production, is up‐regulated in cells overexpressing RAGE and in RAGE‐injected brains of Tg2576 mice, the molecular mechanisms underlying RAGE, BACE1 expression, and Aβ production were examined. Because RAGE stimulates intracellular calcium, nuclear factor of activated T‐cells 1 (NFAT1) was examined. NFAT1 was activated following RAGE‐induced BACE1 expression followed by Aβ generation. Injection of soluble RAGE (sRAGE), which acts as a competitor with full‐length RAGE (fRAGE), into aged Tg2576 mouse brains reduced the levels of plaques, A.,BACE1, and the active form of NFAT1 compared with fRAGE‐injected Tg2576 mice. Taken together, RAGE stimulates functional BACE1 expression through NFAT1 activation, resulting in more Aβ production and deposition in the brain.— Cho, H. J., Son, S. M., Jin, S. M., Hong, H. S., Shin, D. H., Kim, S. J., Huh, K., Mook‐Jung, I. RAGE regulates BACE1 and Aβ generation via NFAT1 activation in Alzheimers disease animal model. FASEBJ. 23, 2639–2649 (2009)