Alzheimer Disease: Liu L

Wang JM, Irwin RW, Liu L, Chen S, Brinton RD. · Department of Pharmacology and Pharmaceutical Sciences and Program in Neuroscience, University of Southern California, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA 90089, USA. · Curr Alzheimer Res. · Pubmed #18220513 No free full text.

Abstract: Confronting the efficacy of a regenerative therapeutic is the degenerative environment that is characterized by neuronal loss, physical plague and glial scar barriers and inflammation. But perhaps more fundamental from a regenerative perspective, are changes in the biochemical milieu of steroid and peptide growth factors, cytokines and neurotransmitter systems. Data from multiple levels of analysis indicate that gonadal steroid hormones and their metabolites can promote neural health whereas their decline or absence are associated with decline in neural health and increased risk of neurodegenerative disease including Alzheimer's. Among the steroids in decline, is allopregnanolone (APbeta, a neurosteroid metabolite of progesterone, which was found to be reduced in the serum [1,2] and plasma [3] and brain of aged vs. young subjects [4]. Further, Alzheimer disease (AD) victims showed an even further reduction in plasma and brain levels of APalpha relative to age-matched neurologically normal controls [1,4,5]. Our earlier work has shown that APalpha is a neurogenic agent for rodent hippocampal neural progenitors and for human neural progenitor cells derived from the cerebral cortex[6]. Our ongoing research seeks to determine the neurogenic potential of APalpha in the triple transgenic mouse model of Alzheimer's disease (3xTgAD) as AD related pathology progresses from imperceptible to mild to severe. Initial analyses suggest that neurogenic potential changes with age in nontransgenic mice and that the neurogenic profile differs between non-transgenic and 3xTgAD mice. Comparative analyses indicate that APalpha modifies neurogenesis in both nontransgenic and 3xTgAD mice. Preliminary data suggest that APalpha may modify Alzheimer's pathology progression. Together the data indicate that APalpha may maintain the regenerative ability of the brain and modify progression of AD related pathology. Challenges for efficacy of regenerative agents within a degenerative milieu are discussed.

Wang JM, Liu L, Irwin RW, Chen S, Brinton RD. · Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA 90089-9121, USA. · Brain Res Rev. · Pubmed #17931704 No free full text.

Abstract: The neuroendocrine status of the brain has been linked to the quality of the aging process, to the risk of Alzheimer's disease and to progression of neurodegenerative pathology. Data from multiple levels of analysis ranging from in vitro cellular models to in vivo animal models to clinical investigations indicate that the decline of neurosteroids play a key role in successful aging and prevention of neurodegenerative disease Alzheimer's. Among the neurosteroids in decline during aging is allopregnanolone (APalpha, a metabolite of progesterone, which is reduced in the serum, plasma and brain of aged vs. young subjects. Further, Alzheimer's disease (AD) victims exhibit an even greater reduction in plasma and brain levels of APalpha relative to age-matched neurologically normal controls. Our earlier work has shown that APalpha is a neurogenic agent for rodent hippocampal neural progenitors and for human neural progenitor cells derived from the cerebral cortex. Our ongoing research seeks to determine the neurogenic potential of APalpha in the triple transgenic mouse model of Alzheimer's disease (3 x TgAD) as AD related pathology progresses from imperceptible to mild to severe. Initial analyses suggest that APalpha may maintain the regenerative ability of the brain, modify progression of AD related pathology and reverse learning and memory deficits in 3 x TgAD mice. This review summarizes current APalpha research in different animal models, neural progenitor regeneration within a degenerative milieu and the challenge for developing neuroregenerative therapeutics.

Komatsu H, Liu L, Murray IV, Axelsen PH. · The Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Biochim Biophys Acta. · Pubmed #17632073 No free full text.

Abstract: The fully developed lesion of Alzheimer's disease is a dense plaque composed of fibrillar amyloid beta-proteins (Abeta) with a characteristic and well-ordered beta-sheet secondary structure. Because the incipient lesion most likely develops when these proteins are first induced to form beta-sheet structure, it is important to understand factors that induced Abeta to adopt this conformation. In this review, we describe the application of polarized attenuated total internal reflection infrared FT-IR spectroscopy for characterizing the conformation, orientation, and rate of accumulation of Abeta on lipid membranes. We also describe the application and yield of linked analysis, whereby multiple spectra are fit simultaneously with component bands that are constrained to share common fitting parameters. Results have shown that membranes promote beta-sheet formation under a variety of circumstances that may be significant to the pathogenesis of Alzheimer's disease.

Ulrey CL, Liu L, Andrews LG, Tollefsbol TO. · Department of Biology, University of Alabama at Birmingham, 35294, USA. · Hum Mol Genet. · Pubmed #15809266 links to  free full text

Abstract: Methylation of genomic cytosines is one of the best characterized epigenetic mechanisms, and investigation of its relationship with other biochemical pathways represents a critical stage in the elucidation of biological information processing. The field also has immense potential for the development of medical treatments for any number of conditions ranging from aging to neurological disorders. The DNA methylation status of genes is responsible for many heritable traits and varies more or less independently of the genetic code. This variation is often a result of cellular environmental factors including metabolism. A key metabolite in this regard is homocysteine. Knowledge of homocysteine metabolism continues to be amassed, yet the part played by aberrant DNA methylation in homocysteine-related pathologies is often, at best, conjectural. In this analysis, we will review recent insights and attempt to speculate meaningfully concerning the dynamics of the methionine cycle in relation to DNA methylation and disease.

Cooke JR, Loredo JS, Liu L, Marler M, Corey-Bloom J, Fiorentino L, Harrison T, Ancoli-Israel S. · Department of Medicine, University of California, San Diego, California, USA. · Drugs Aging. · Pubmed #16872233 No free full text.

Abstract: BACKGROUND AND OBJECTIVE: Studies suggest that some acetylcholinesterase inhibitors (AChEIs) increase rapid eye movement (REM) sleep and nightmares in patients with Alzheimer's disease (AD) but few have studied their effect on other sleep parameters. The objective of this study was to examine differences in sleep architecture in AD patients taking different AChEIs. METHODS: 76 participants (51 men, 25 women) [mean age = 78.2 years; SD = 7.7] with mild to moderate AD underwent medication history screening as well as polysomnography to determine the percentage of each sleep stage. Participants were divided into groups based on AChEI used: donepezil (n = 41), galantamine (n = 15), rivastigmine (n = 8) or no AChEI (n = 12). General univariate linear model analyses were performed. RESULTS: AChEI therapy had a significant effect on the percentage of stage 1 (p = 0.01) and stage 2 (p = 0.03) sleep. Patients in the donepezil group had a significantly lower percentage of stage 1 sleep than patients in the galantamine group (mean = 17.3%, SD = 11.7 vs 29.2%, SD = 15.0, respectively; p = 0.01), but there was no significant difference between the donepezil group and the rivastigmine (mean = 25.0%, SD = 12.3) or no AChEI groups (mean = 27.6%, SD = 17.7) in this respect. No significant differences in percentage of stage 1 between other groups were seen. Patients in the donepezil group also had a significantly higher percentage of stage 2 sleep than patients in the no AChEI group (mean = 63.6%, SD = 14.4 vs 51.4%, SD = 16.9, respectively; p = 0.04), but there was no significant difference between the donepezil group and either the galantamine group (mean = 56.5%, SD = 8.7) or the rivastigmine group (mean = 59.9%, SD = 8.4). There were no significant differences between groups in terms of percentage REM sleep or other sleep parameters. CONCLUSION: Subgroups of AD patients (classified according to AChEI treatment) in this study differed with respect to the amount of stage 1 and stage 2 sleep experienced, with the donepezil-treated group having the lowest percentage of stage 1 sleep and the highest percentage of stage 2 sleep. There was no significant difference in the amount of REM sleep between the groups. Our data suggest that sleep architecture may be affected by the use of donepezil in patients with AD. Although not elicited in this study because of the small sample size, there may be a class effect of AChEIs on sleep architecture. Double-blind, placebo-controlled studies are needed to better understand causality and the effect of each AChEI on sleep architecture in patients with AD.

Planel E, Krishnamurthy P, Miyasaka T, Liu L, Herman M, Kumar A, Bretteville A, Figueroa HY, Yu WH, Whittington RA, Davies P, Takashima A, Nixon RA, Duff KE. · Taub Institute for Alzheimer's Disease Research, Department of Pathology, Columbia University Medical Center, New York, New York 10032, USA. · J Neurosci. · Pubmed #19036972 links to  free full text

Abstract: In Alzheimer's disease, tau is hyperphosphorylated, which is thought to detach it from microtubules (MTs), induce MT destabilization, and promote aggregation. Using a previously described in vivo model, we investigated whether hyperphosphorylation impacts tau function in wild-type and transgenic mice. We found that after anesthesia-induced hypothermia, MT-free tau was hyperphosphorylated, which impaired its ability to bind MTs and promote MT assembly. MT-bound tau was more resistant to hyperphosphorylation compared with free tau and tau did not dissociate from MTs in wild-type mice. However, 3-repeat tau detached from MT in the transgenic mice. Surprisingly, dissociation of tau from MTs did not lead to overt depolymerization of tubulin, and there was no collapse, or disturbance of axonal MT networks. These results indicate that, in vivo, a subpopulation of tau bound to MTs does not easily dissociate under conditions that extensively phosphorylate tau. Tau remaining on the MTs under these conditions is sufficient to maintain MT network integrity.

Ancoli-Israel S, Palmer BW, Cooke JR, Corey-Bloom J, Fiorentino L, Natarajan L, Liu L, Ayalon L, He F, Loredo JS. · Departments of Psychiatry, University of California, San Diego, La Jolla, California, USA. · J Am Geriatr Soc. · Pubmed #18795985 No free full text.

Abstract: OBJECTIVES: To examine whether treatment of obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP) in patients with Alzheimer's disease (AD) results in better cognitive function. DESIGN: Randomized double-blind placebo-controlled trial. Participants were randomized to therapeutic CPAP for 6 weeks or placebo CPAP for 3 weeks followed by therapeutic CPAP for 3 weeks. SETTING: General clinical research center. PARTICIPANTS: Fifty-two men and women with mild to moderate AD and OSA. INTERVENTION: CPAP. MEASUREMENTS: A complete neuropsychological test battery was administered before treatment and at 3 and at 6 weeks. RESULTS: A comparison of subjects randomized to 3 weeks of therapeutic versus placebo CPAP suggested no significant improvements in cognition. A comparison of pre- and posttreatment neuropsychological test scores after 3 weeks of therapeutic CPAP in both groups showed a significant improvement in cognition. The study was underpowered to make definitive statements about improvements within specific cognitive constructs, although exploratory post hoc examination of change scores for individual tests suggested improvements in episodic verbal learning and memory and some aspects of executive functioning such as cognitive flexibility and mental processing speed. CONCLUSION: OSA may aggravate cognitive dysfunction in dementia and thus may be a reversible cause of cognitive loss in patients with AD. OSA treatment seems to improve some cognitive functioning. Clinicians who care for patients with AD should consider implementing CPAP treatment when OSA is present.

Barger SW, DeWall KM, Liu L, Mrak RE, Griffin WS. · Department of Geriatrics, Geriatric Research Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA. · J Neuropathol Exp Neurol. · Pubmed #18648325 No free full text.

Abstract: Theories regarding the initiation and progression of Alzheimer disease (AD) often consider potential roles played by elevations of beta-amyloid precursor protein (betaAPP). Because it is the source of amyloid beta-peptide, betaAPP may simply contribute more pathogenic stimulus when elevated; some analyses have, however, reported a decline in betaAPP in AD. We found a progressive increase in neuronal betaAPP expression with increasing age in the brains of nondemented individuals, whereas in AD patient samples, betaAPP antigenicity decreased in neuronal somata in a manner that correlated with accumulation of mature amyloid beta-peptide plaques. In contrast, apolipoprotein E (ApoE) expression correlated with accumulation of plaques, and even greater amounts of ApoE were detected in plaques. Induction of betaAPP by glutamate in neuronal cell cultures was found to depend upon ApoE levels or activity. Thus, elevations in expression of ApoE and betaAPP by cellular stresses are likely normally linked in vivo, and uncoupling of this link, or other pathologic events in AD initiation, may leave neurons with diminished betaAPP expression, which might in turn reduce their resistance to stressors.

Liu L, Orozco IJ, Planel E, Wen Y, Bretteville A, Krishnamurthy P, Wang L, Herman M, Figueroa H, Yu WH, Arancio O, Duff K. · Department of Pathology, Taub Institute for Research on Alzheimer's Disease, Columbia University, Black Building #5-513, 650 West 168th Street, New York, NY 10032, USA. · Neurobiol Dis. · Pubmed #18504134 No free full text.

Abstract: In the last decade, multiple lines of transgenic APP overexpressing mice have been created that recapitulate certain aspects of Alzheimer's disease (AD). However, none of the previously reported transgenic APP overexpressing rat models developed AD-like beta-amyloid (Abeta) deposits, or age-related learning and memory deficits. In the present study, we have characterized a transgenic rat model overexpressing transgenes with three, familial AD mutations (two in APP and one in PS1) that were developed by Flood et al. [Flood, D.G., et al., Abeta deposition in a transgenic rat model of Alzheimer's disease. Society for Neuroscience 2003, Washington, DC, 2003]. From the age of 9 months, these rats develop Abeta deposits in both diffuse and compact forms, with the latter being closely associated with activated microglia and reactive astrocytes. Impaired long-term potentiation (LTP) was revealed by electrophysiological recordings performed on hippocampal slices from rats at 7 months of age, which is 2 months before the appearance of amyloid plaques. The deficit in LTP was accompanied by impaired spatial learning and memory in the Morris water maze, which became more pronounced in transgenic rats of 13 months of age. For Tg rats of both ages, there was a trend for cognitive impairment to correlate with total Abeta42 levels in the hippocampus. The rat model therefore recapitulates AD-like amyloid pathology and cognitive impairment. The advantage of the rat model over the available mouse models is that rats provide better opportunities for advanced studies, such as serial CSF sampling, electrophysiology, neuroimaging, cell-based transplant manipulations, and complex behavioral testing.

Murray IV, Liu L, Komatsu H, Uryu K, Xiao G, Lawson JA, Axelsen PH. · Department of Pharmacology, Center for Neurodegenerative Disease Research, Penn Genomics Institute, University of Pennsylvania, Philadelphia, PA 19104, USA. · J Biol Chem. · Pubmed #17255094 links to  free full text

Abstract: Evidence of oxidative stress and the accumulation of fibrillar amyloid beta proteins (Abeta) in senile plaques throughout the cerebral cortex are consistent features in the pathology of Alzheimer disease. To define a mechanistic link between these two processes, various aspects of the relationship between oxidative lipid membrane damage and amyloidogenesis were characterized by chemical and physical techniques. Earlier studies of this relationship demonstrated that oxidatively damaged synthetic lipid membranes promoted amyloidogenesis. The studies reported herein specify that 4-hydroxy-2-nonenal (HNE) is produced in both synthetic lipids and human brain lipid extracts by oxidative lipid damage and that it can account for accelerated amyloidogenesis. Abeta promotes the copper-mediated generation of HNE from polyunsaturated lipids, and in turn, HNE covalently modifies the histidine side chains of Abeta. HNE-modified Abeta have an increased affinity for lipid membranes and an increased tendency to aggregate into amyloid fibrils. Thus, the prooxidant activity of Abeta leads to its own covalent modification and to accelerated amyloidogenesis. These results illustrate how lipid membranes may be involved in templating the pathological misfolding of Abeta, and they suggest a possible chemical mechanism linking oxidative stress with amyloid formation.

Cooke JR, Liu L, Natarajan L, He F, Marler M, Loredo JS, Corey-Bloom J, Palmer BW, Greenfield D, Ancoli-Israel S. · Department of Medicine, University of California, San Diego, Veterans Affairs San Diego Healthcare System, CA, USA. · Behav Sleep Med. · Pubmed #17083302 No free full text.

Abstract: Patients with Alzheimer's disease (AD) commonly have poor sleep and a high reported incidence of sleep-disordered breathing (SDB). This study examined how the presence of SDB affected sleep stages in AD patients. Sixty-six volunteers with mild - moderate AD underwent home polysomnography. Results showed that patients with SDB spent less of the night in REM sleep than those with no SDB, but there were no differences in other sleep stages. The findings suggest that the decreased amount of REM sleep may be due to the presence of AD and SDB. Treating these patients' SDB may increase their amount of REM sleep, which may result in improved daytime functioning. Controlled trials of SDB treatment in AD are needed to answer this question.

Stewart M, Barnfather A, Neufeld A, Warren S, Letourneau N, Liu L. · Faculty of Nusing, University of Alberta, Canada. · Can J Aging. · Pubmed #16821200 No free full text.

Abstract: Accessible support programs can improve health outcomes for family caregivers of older relatives with a chronic condition. Over the course of 6 months, 27 experienced family caregivers provided weekly support via the telephone to 66 individuals, either new family caregivers of seniors recently diagnosed with stroke or newly vulnerable family caregivers (i.e., facing increasing demands from the deterioration of their senior relative's condition) of seniors with Alzheimer's disease. Qualitative data documented the perceived impact of the intervention, including increased satisfaction with support, coping skills, caregiving competence and confidence, and decreased caregiver burden and loneliness. Caregivers identified varied support processes that overcame support deficits in their social networks. These processes can facilitate replication in future research and inform practice, programs, and policies.

Chong MS, Ayalon L, Marler M, Loredo JS, Corey-Bloom J, Palmer BW, Liu L, Ancoli-Israel S. · Department of Psychiatry, Univeristy of California at San Diego, San Diego, CA 92161, USA. · J Am Geriatr Soc. · Pubmed #16696743 No free full text.

Abstract: OBJECTIVES: Studies have reported that 33% to 70% of patients with Alzheimer's disease (AD) have sleep-disordered breathing (SDB). Continuous positive airway pressure (CPAP) treatment has been shown to reduce daytime sleepiness and improve health-related quality of life in nondemented older people with SDB. The effect of therapeutic CPAP treatment on daytime sleepiness in patients with mild-moderate AD with SDB was assessed. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Patients' home and the University of California San Diego, General Clinical Research Center, J. Christian Gillin Laboratory of Sleep and Chronobiology. PARTICIPANTS: Thirty-nine community-dwelling elderly patients with mild-moderate probable AD with SDB. INTERVENTION: Patients were randomly assigned to receive 6 weeks of therapeutic CPAP or 3 weeks of sham CPAP followed by 3 weeks of therapeutic CPAP. MEASUREMENTS: Epworth Sleepiness Scale (ESS) was administered at baseline, 3 weeks, and 6 weeks. Changes in daytime sleepiness in subjects who received optimal therapeutic CPAP were compared with changes in the sham CPAP group. RESULTS: Within the therapeutic CPAP group, ESS scores were reduced from 8.89 during baseline to 6.56 after 3 weeks of treatment (P=.04) and to 5.53 after 6 weeks of treatment (P=.004). In the sham CPAP group, there was no significant difference after 3 weeks of sham CPAP but a significant decrease from 7.68 to 6.47 (P=.01) after 3 weeks of therapeutic CPAP. CONCLUSION: These data provide evidence of the effectiveness of CPAP in reducing subjective daytime sleepiness in patients with AD with SDB.

Griffin WS, Liu L, Li Y, Mrak RE, Barger SW. · Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. · J Neuroinflammation. · Pubmed #16542445 links to  free full text

Abstract: BACKGROUND: Clinical and neuropathological overlap between Alzheimer's (AD) and Parkinson's disease (PD) is now well recognized. Such cases of concurrent AD and Lewy body disease (AD/LBD) show neuropathological changes that include Lewy bodies (alpha-synuclein aggregates), neuritic amyloid plaques, and neurofibrillary tangles (hyperphosphorylated tau aggregates). The co-occurrence of these clinical and neuropathological changes suggests shared pathogenic mechanisms in these diseases, previously assumed to be distinct. Glial activation, with overexpression of interleukin-1 (IL-1) and other proinflammatory cytokines, has been increasingly implicated in the pathogenesis of both AD and PD. METHODS: Rat primary cultures of microglia and cortical neurons were cultured either separately or as mixed cultures. Microglia or cocultures were treated with a secreted fragment (sAPPalpha) of the beta-amyloid precursor protein (betaAPP). Neurons were treated with IL-1beta or conditioned medium from sAPPalpha-activated microglia, with or without IL-1 receptor antagonist. Slow-release pellets containing either IL-1beta or bovine serum albumin (control) were implanted in cortex of rats, and mRNA for various neuropathological markers was analyzed by RT-PCR. Many of the same markers were assessed in tissue sections from human cases of AD/LBD. RESULTS: Activation of microglia with sAPPalpha resulted in a dose-dependent increase in secreted IL-1beta. Cortical neurons treated with IL-1beta showed a dose-dependent increase in sAPPalpha release, an effect that was enhanced in the presence of microglia. IL-1beta also elevated the levels of alpha-synuclein, activated MAPK-p38, and phosphorylated tau; a concomitant decrease in levels of synaptophysin occurred. Delivery of IL-1beta by slow-release pellets elevated mRNAs encoding alpha-synuclein, betaAPP, tau, and MAPK-p38 compared to controls. Finally, human cases of AD/LBD showed colocalization of IL-1-expressing microglia with neurons that simultaneously overexpressed betaAPP and contained both Lewy bodies and neurofibrillary tangles. CONCLUSION: Our findings suggest that IL-1 drives production of substrates necessary for formation of the major neuropathological changes characteristic of AD/LBD.

Ayalon L, Ancoli-Israel S, Stepnowsky C, Marler M, Palmer BW, Liu L, Loredo JS, Corey-Bloom J, Greenfield D, Cooke J. · Department of Psychiatry, University of California, San Diego, San Diego, CA, and Veterans Affairs San Diego Health Care System, San Diego, CA 92161, USA. · Am J Geriatr Psychiatry. · Pubmed #16473983 No free full text.

Abstract: OBJECTIVE: This analysis examined whether patients with Alzheimer disease (AD) tolerate continuous positive airway pressure (CPAP). METHOD: Thirty patients with AD were randomized to CPAP or sham CPAP and completed sleep, depression, and quality-of-life questionnaires. Participants could choose to continue treatment after the trial. RESULTS: Patients wore CPAP for 4.8 hours per night. More depressive symptoms were associated with worse adherence (rS=-0.37; N=30, p<0.04). Patients who continued using CPAP had fewer depressive symptoms (t [19]=2.45, p=0.02) and better adherence (t [19]=2.32, p=0.03) during the trial. CONCLUSION: Patients with AD with obstructive sleep apnea can tolerate CPAP. Adherence and long-term use may be more difficult among those patients with more depressive symptoms.

Liu L, Li Y, Van Eldik LJ, Griffin WS, Barger SW. · Department of Geriatrics, University of Arkansas for Medical Sciences, 629 Jack Stephens Drive #807, Little Rock, AR 72205, USA. · J Neurochem. · Pubmed #15659225 No free full text.

Abstract: Both the astrocytic cytokine S100B and the pro-inflammatory interleukin-1 (IL-1) are elevated in Alzheimer's disease, and each has been implicated in Alzheimer-related neuropathology. We examined the gene-regulatory events through which S100B induces IL-1beta expression. In primary microglia, S100B activated the transcription factors Sp1 and NFkappaB, followed by an increase in IL-1beta mRNA levels. The latter was blocked by a peptide inhibitor of NFkappaB or by a double-stranded oligonucleotide containing a NFkappaB-binding site to serve as "decoy" DNA and reduce available NFkappaB. But in primary cortical neurons, decoy and siRNA experiments indicated that the IL-1beta induction by S100B was mediated by Sp1 without evidence of a role for NFkappaB. Our results suggest that the elevation of S100B and IL-1 in Alzheimer brain and consequent neurodegenerative events are mediated through cell-type specific gene-regulatory events, providing mechanistic insight into connections between glial activation and neuronal dysfunction.

Li Y, Liu L, Liu D, Woodward S, Barger SW, Mrak RE, Griffin WS. · Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. · J Neuroimmunol. · Pubmed #14741427 No free full text.

Abstract: The fate of the fragmented DNA (fDNA) observed in neuronal nuclei in Alzheimer brain is unknown. However, its fate is suggested as fDNA is found in the cytoplasm of adjacent activated microglia. After a brief incubation with fDNA, approximately 70% of microglia had fDNA in their cytoplasm, were activated, and overexpressed interleukin-1beta. Microglial activation enhanced uptake whereas blocking scavenger receptors suppressed this uptake. These results suggest that the brain rids itself of fDNA from dying neurons through microglial uptake, activation, and overexpression of IL-1. Such overexpression of IL-1 in Alzheimer brain has been linked to Alzheimer pathogenesis.

van Groen T, Liu L, Ikonen S, Kadish I. · Department of Neuroscience and Neurology, University of Kuopio, Canthia Building, PO Box 1627, 70211, Kuopio, Finland. · Neuroscience. · Pubmed #12831872 No free full text.

Abstract: Alzheimer's disease (AD) is the most common form of dementia in the elderly, and the characteristic pathological hallmarks of the disease are neuritic plaques and neurofibrillary tangles. The sequence of events leading to the extracellular deposition of amyloidbeta (Abeta) peptides in plaques or in diffuse deposits is not clear. Here we investigate the relation between disrupted axonal transport of amyloid precursor protein (APP) and/or Abeta and the deposition of Abeta in the deafferented terminal fields in APP/presenilin 1 double-transgenic AD-model mice. In the first experiment we ablated entorhinal cortex neurons and examined the subsequent changes in amyloid deposition in the hippocampus 1 month later. We show that there is a substantial reduction in the amount of diffuse amyloid deposits in the denervated areas of the hippocampus. Further, to investigate the effects of long-term deafferentation, in a second experiment we cut the fimbria-fornix and analyzed the brains 11 months post-lesion. Diffuse amyloid deposits in the deafferented terminal fields of area CA1 and subiculum were dramatically reduced as assessed by image analysis of the Abeta load. Our findings indicate that neuronal ablations decrease diffuse amyloid deposits in the terminal fields of these neurons, and, further, that pathway lesions similarly decrease the amount of diffuse amyloid deposits in the terminal fields of the lesioned axons. Together, this suggests that the axonal transport of APP and/or Abeta and subsequent secretion of Abeta at terminals plays an important role in the deposition of Abeta protein in Alzheimer's disease, and, further, that diffuse deposits do not develop into plaques.py>

Liu L, Tapiola T, Herukka SK, Heikkilä M, Tanila H. · Department of Neuroscience, University of Kuopio, PO Box 1627, 70211 Kuopio, Finland. · Neuroreport. · Pubmed #12544850 No free full text.

Abstract: We compared beta-amyloid peptide (Abeta) levels in the serum, CSF and brain (hippocampus) and correlated these with spatial learning in APP+PS1 transgenic mice. Compared with non-transgenic littermates, male 14-month-old APP + PS1 mice were impaired in spatial learning in the water maze. Among the APP + PS1 mice, only the hippocampal insoluble Abeta42 level correlated with spatial memory (r = -0.44). The levels of insoluble Abeta40 and Abeta42 were highly correlated (r = 0.92), and also correlated with soluble hippocampal Abeta42 (r = 0.64/0.69), which further correlated with the CSF Abeta42 (r = 0.52). None of these parameters correlated with serum Abeta40 levels. These findings support the role of insoluble Abeta42 in memory dysfunction and suggest a model with several pools (insoluble, extracellular soluble, CSF) of Abeta being in partial equilibrium with each other.

Liu L, Ikonen S, Tapiola T, Tanila H, van Groen T. · Department of Neuroscience and Neurology, University of Kuopio, FIN 70211, Kuopio, Finland. · Exp Neurol. · Pubmed #12429202 No free full text.

Abstract: The deposition of amyloid beta peptides (Abeta) and cholinergic dysfunction are two characteristic features of Alzheimer's disease. Several studies have suggested that a compromised cholinergic transmission can increase the amount of amyloid precursor protein (APP) in the denervated cortex (or hippocampus); however, whether this will increase Abeta production is unknown. To investigate the relation between cholinergic neurotransmission and APP metabolism, and the possible role of cholinergic dysfunction in the development of amyloid neuropathology, we lesioned the fimbria-fornix pathway in APP+PS1 double transgenic mice, at 5 and 7 months of age. Three months and 11 months postlesion, the mice were sacrificed for biochemical and histopathological analyses. The fimbria-fornix transection resulted in a substantial depletion of cholinergic markers in the hippocampus at both time points. Three months postlesion, hippocampal APP and Abeta levels were not significantly changed. At 11 months postlesion, the fimbria-fornix lesion did not result in an alteration in either the hippocampal Abeta levels or the extent of Abeta deposition, as assessed by amyloid plaque counts and image analysis of Abeta load in the 18-month-old APP+PS1 mice. Our findings indicate that APP metabolism in mice may be dissociated from cholinergic neurotransmission rather than related as previously suggested in other mammalian species.

Liu L, Ikonen S, Heikkinen T, Heikkilä M, Puoliväli J, van Groen T, Tanila H. · Department of Neuroscience and Neurology, University of Kuopio/Canthia, PO Box 1627, 70211 Kuopio, Finland. · Behav Brain Res. · Pubmed #12191831 No free full text.

Abstract: Transgenic mice carrying mutated human amyloid precursor protein (APPswe) and presenilin (PS1, A246E) genes develop first amyloid plaques around 9 months of age, but up to 18 months of age, amyloid depositions in these mice were largely restricted to the hippocampus, subiculum, and neocortex. To assess the behavioral consequences of amyloid accumulation in the hippocampal formation, we compared the effects of APP+PS1 (AP) genotype and fimbria-fornix (FFX) transection, either alone or combined, on various spatial learning and memory tasks. Both FFX-lesioned and AP mice were impaired in spatial navigation in the water maze, a typical hippocampal dependent task. Conversely, neither group of mice was impaired in a win-stay version of the radial arm maze (RAM) or position discrimination in the T-maze, tasks that do not depend on the hippocampus. FFX-lesioned mice were impaired in the win-shift version of the RAM, and in spontaneous and rewarded alternation in the T-maze, while AP mice performed equal to non-transgenic controls in all these working memory tasks, except long-term retention of the RAM task. AP mice thus appear to have a selective deficit in hippocampal dependent long-term memory, as do Alzheimer patients at early stage of the disease.

Liu L, Ikonen S, Heikkinen T, Tapiola T, van Groen T, Tanila H. · Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland. · Exp Neurol. · Pubmed #11822883 No free full text.

Abstract: Recent studies in cell cultures have shown that modulating the cholinergic activity can influence the processing and metabolism of amyloid precursor protein (APP). To investigate whether acetylcholinesterase inhibitors (ChEIs) could decrease production of amyloid beta-peptide (A(beta)) and slow down the accumulation of A(beta) also in vivo, we chronically administered metrifonate (100 mg/kg, po), a second-generation ChEI, to 7-month-old doubly transgenic APP+PS1 mice and their nontransgenic littermate controls for 7 months. Behavioral studies, including open field test, T maze, and water maze, were conducted after 6 months treatment with metrifonate, and the mice were sacrificed at the age of 14 months for biochemical and histological analyses. The long-term treatment with metrifonate failed to inhibit the marked overproduction and deposition of A(beta) in the APP+PS1 mice; in contrast, it increased both A(beta)40 and A(beta)42 levels in the hippocampus. However, the A(beta)42 to 40 ratio was significantly reduced by the treatment. In addition, the number of amyloid plaques in the hippocampus did not differ between the treatment and the control groups. Tolerance to cholinesterase inhibition might be induced in the mouse brain because the inhibition rate of AChE was attenuated from about 80 to 50% during the experiment in both APP+PS1 and nontransgenic mice. The metrifonate treatment did not affect cognitive testing parameters but reduced swimming speed and locomotor activity in both genotypes. Our results do not support the idea that ChEIs would slow down the progression of amyloid pathology in Alzheimer's disease.

Warren S, Janzen W, Andiel-Hett C, Liu L, McKim HR, Schalm C. · Faculty of Rehabilitation Medicine, Room 348 Corbett Hall, University of Alberta, Edmonton, Alberta T6G 2G4, Canada. · Dement Geriatr Cogn Disord. · Pubmed #11455135 No free full text.

Abstract: Residential care centres (RCCs) for persons with Alzheimer disease are increasing worldwide, but there are few studies that compare the functional outcomes of RCC residents to residents of other types of continuing care settings. This study compared residents of the first Canadian RCC on physical, cognitive, behavioural and emotional functioning 6, 12 and 18 months after admission to residents of special care units (SCUs) operated by the same continuing care provider. SCU residents were initially functioning lower than RCC residents on most outcome measures and these differences persisted over time. Resident functioning declined over time regardless of care setting and, when the initial status was controlled for, the rates of decline were similar. However, RCC residents experienced greater independence/freedom of choice, fewer physical or psychotropic medication restraints and were more active, which may have enhanced their quality of life.

Xu W, Liu L, Emson P, Harrington CR, McKeith IG, Perry RH, Morris CM, Charles IG. · The Wolfson Institute for Biomedical Research, London, UK. · Neuroreport. · Pubmed #10674474 No free full text.

Abstract: We report the analysis of the allele distribution of a (CCTTT)n pentanucleotide repeat within the promoter region of the NOS2A gene in DNA samples from patients with autopsy confirmed Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) type. A significant difference was observed in the allelic distribution between the control group and the DLB group (chi2 = 15.175, df = 5; p<0.01), with an increased occurrence of the eight and nine repeat alleles, and a marked under representation of the 11 repeat allele. Genotype frequencies in the DLB group also differed significantly from controls (p<0.012). These results suggest that variations in the NOS2A gene may predispose to the development of DLB.

Li Y, Liu L, Kang J, Sheng JG, Barger SW, Mrak RE, Griffin WS. · Donald W. Reynolds Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. · J Neurosci. · Pubmed #10627591 links to  free full text

Abstract: Cholinergic dysfunction in Alzheimer's disease has been attributed to stress-induced increases in acetylcholinesterase (AChE) activity. Interleukin-1 (IL-1) is overexpressed in Alzheimer's disease, and stress-related changes in long-term potentiation, an ACh-related cerebral function, are triggered by interleukin-1. Microglial cultures (N9) synthesized and released IL-1 in response to conditioned media obtained from glutamate-treated primary neuron cultures or PC12 cells. This conditioned media contained elevated levels of secreted beta-amyloid precursor protein (sAPP). Naive PC12 cells cocultured with stimulated N9 cultures showed increased AChE activity and mRNA expression. These effects on AChE expression and activity could be blocked by either preincubating the glutamate-treated PC12 supernatants with anti-sAPP antibodies or preincubating naive PC12 cells with IL-1 receptor antagonist. These findings were confirmed in vivo; IL-1-containing pellets implanted into rat cortex also increased AChE mRNA levels. Neuronal stress in Alzheimer's disease may induce increases in AChE expression and activity through a molecular cascade that is mediated by sAPP-induced microglial activation and consequent overexpression of IL-1.