Biomedical subjects

D Allan Butterfield

Publications and source records attributed to D Allan Butterfield.

At least 37 records · Page 2Linked to original sources

PubMed2006

Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: insights into the development of Alzheimer's disease.

Mild cognitive impairment (MCI) is generally referred to the transitional zone between normal cognitive function and early dementia or clinically probable Alzheimer's disease (AD). Oxidative stress plays a significant role in AD and is increased in the superior/middle temporal gyri of MCI subjects. Because AD involves hippocampal-resident memory dysfunction, we determined protein oxidation and identified the oxidized proteins in the hippocampi of MCI subjects. We found that protein oxidation is significantly increased in the hippocampi of MCI subjects when compared to age- and sex-matched controls. By using redox proteomics, we determined the oxidatively modified proteins in MCI hippocampus to be alpha-enolase (ENO1), glutamine synthetase (GLUL), pyruvate kinase M2 (PKM2) and peptidyl-prolyl cis/trans isomerase 1 (PIN1). The interacteome of these proteins revealed that these proteins functionally interact with SRC, hypoxia-inducible factor 1, plasminogen (PLG), MYC, tissue plasminogen activator (PLAT) and BCL2L1. Moreover, the interacteome indicates the functional involvement of energy metabolism, synaptic plasticity and mitogenesis/proliferation. Therefore, oxidative inactivation of ENO1, GLUL and PIN1 may alter these cellular processes and lead to the development of AD from MCI. We conclude that protein oxidation plays a significant role in the development of AD from MCI and that the oxidative inactivation of ENO1, GLUL, PKM2 and PIN1 is involved in the progression of AD from MCI. The current study provides a framework for future studies on the development of AD from MCI relevant to oxidative stress.

Aged↗

PubMed2006

Low molecular weight thiol amides attenuate MAPK activity and protect primary neurons from Abeta(1-42) toxicity.

Oxidative stress caused by various stimuli lead to oxidation of glutathione (GSH), the major redox power of the cell. Amyloid beta [Abeta(1-42)] is one of the key components of senile plaques and is involved in the progress initiation and triggers of Alzheimer's disease (AD). Lower GSH levels correlated with the activation of mitogen-activated proteins kinases (MAPK) have been demonstrated in AD, Parkinson's disease (PD) and other neurodegenerative disorders and have been proposed to play a central role in the deterioration of the aging and neurodegenerative brain. In this study, we evaluated the ability of low molecular weight thiol amides, N-acetyl cysteine amide (AD4) that replenishes GSH levels, N-acetyl glycine cysteine amide (AD7) and N-acetyl-Cys-Gly-Pro-Cys-amide (CB4) to protect primary neuronal culture against the oxidative and neurotoxic effects of Abeta(1-42) and to inhibit cisplatin- and hydrogen-peroxide-induced phosphorylation of two MAP kinases (MAPK), p38 and ERK1/2, in NIH3T3 cells. Cell death induced by Abeta(1-42) in primary neuronal cells was reversed by the thiol amides. Likewise, protein oxidation, loss of mitochondrial function and DNA fragmentation all returned to control levels by pretreatment with the three thiol amides. Elevated phosphorylation of ERK1/2 and p38 induced by cisplatin or H2O2 in NIH3T3 cells was lowered by AD4, AD7 and CB4 in a dose-dependent manner. Taken together, these results suggest that the thiol amides AD4, AD7 and CB4 protect neuronal cells against Abeta(1-42) toxicity by attenuating oxidative stress in correlation with inhibiting the MAPK phosphorylation cascade. These results are consistent with the notion that these small molecular thiol amides may play a viable protective role in the oxidative and neurotoxicity induced by Abeta(1-42) in AD brain.

Acetylcysteine↗

PubMed2006

Elevated protein-bound levels of the lipid peroxidation product, 4-hydroxy-2-nonenal, in brain from persons with mild cognitive impairment.

Oxidative damage is a feature of many age-related neurodegenerative diseases, including Alzheimer's disease (AD). 4-Hydroxy-2-nonenal (HNE) is a highly reactive product of the free radical-mediated lipid peroxidation of unsaturated lipids, particularly arachidonic acid, in cellular membranes. In the present study we show for the first time in brain obtained at short postmortem intervals that the levels of HNE are elevated in mild cognitive impairment (MCI) hippocampus and inferior parietal lobules compared to those of control brain. Thus, increased levels of HNE in MCI brain implicate lipid peroxidation as an early event in AD pathophysiology and also suggest that the pharmacologic intervention to prevent lipid peroxidation at the MCI stage or earlier may be a promising therapeutic strategy to delay or prevent progression to AD.

Aged, 80 and over↗

PubMed2006

Identification of AGE-modified proteins in SH-SY5Y and OLN-93 cells.

The formation of "Advanced Glycation End products" (AGEs) is an inevitable consequence of mammalian glucose metabolism. AGE-mediated protein-protein crosslinks lead to detergent-insoluble and protease-resistant protein aggregates, and in Alzheimer's disease (AD) extra cellular senile plaques (SPs) and intracellular neurofibrillary tangles (NFTs) have been shown to contain AGEs. However, to date little is known concerning the most prevalent protein-targets of AGE modification under normal, non-pathological conditions. Here, a combination of 2D-electrophoresis, Western blotting and mass spectrometry has been used to identify preferentially AGE-modified proteins in oligodendrocyte (OLN-93) and neuroblastoma cell lines (SH-SY5Y) in standard culture. Proteomics analysis identified a total of eight targets with structural, metabolic and regulatory function, three of which (beta-actin, beta-tubulin and eukaryotic Elongation Factor 1-alpha) were common to both cell lines. Based on results from prior studies, modification of these proteins may lead to a loss of function. Consequently, the identification of targets for these proteins is of particular interest for a better understanding of the consequences of AGE-modification in aging, neurodegenerative diseases and diabetes.

Animals↗

PubMed2006

Redox proteomics in some age-related neurodegenerative disorders or models thereof.

Neurodegenerative diseases cause memory loss and cognitive impairment. Results from basic and clinical scientific research suggest a complex network of mechanisms involved in the process of neurodegeneration. Progress in treatment of such disorders requires researchers to better understand the functions of proteins involved in neurodegenerative diseases, to characterize their role in pathogenic disease mechanisms, and to explore their roles in the diagnosis, treatment, and prevention of neurodegenerative diseases. A variety of conditions of neurodegenerative diseases often lead to post-translational modifications of proteins, including oxidation and nitration, which might be involved in the pathogenesis of neurodegenerative diseases. Redox proteomics, a subset of proteomics, has made possible the identification of specifically oxidized proteins in neurodegenerative disorders, providing insight into a multitude of pathways that govern behavior and cognition and the response of the nervous system to injury and disease. Proteomic analyses are particularly suitable to elucidate post-translational modifications, expression levels, and protein-protein interactions of thousands of proteins at a time. Complementing the valuable information generated through the integrative knowledge of protein expression and function should enable the development of more efficient diagnostic tools and therapeutic modalities. Here we review redox proteomic studies of some neurodegenerative diseases.

Aged↗

PubMed2006

Mutations in amyloid precursor protein and presenilin-1 genes increase the basal oxidative stress in murine neuronal cells and lead to increased sensitivity to oxidative stress mediated by amyloid beta-peptide (1-42), HO and kainic acid: implications for Alzheimer's disease.

Oxidative stress is observed in Alzheimer's disease (AD) brain, including protein oxidation and lipid peroxidation. One of the major pathological hallmarks of AD is the brain deposition of amyloid beta-peptide (Abeta). This 42-mer peptide is derived from the beta-amyloid precursor protein (APP) and is associated with oxidative stress in vitro and in vivo. Mutations in the PS-1 and APP genes, which increase production of the highly amyloidogenic amyloid beta-peptide (Abeta42), are the major causes of early onset familial AD. Several lines of evidence suggest that enhanced oxidative stress, inflammation, and apoptosis play important roles in the pathogenesis of AD. In the present study, primary neuronal cultures from knock-in mice expressing mutant human PS-1 and APP were compared with those from wild-type mice, in the presence or absence of various oxidizing agents, viz, Abeta(1-42), H2O2 and kainic acid (KA). APP/PS-1 double mutant neurons displayed a significant basal increase in oxidative stress as measured by protein oxidation, lipid peroxidation, and 3-nitrotyrosine when compared with the wild-type neurons (p < 0.0005). Elevated levels of human APP, PS-1 and Abeta(1-42) were found in APP/PS-1 cultures compared with wild-type neurons. APP/PS-1 double mutant neuron cultures exhibited increased vulnerability to oxidative stress, mitochondrial dysfunction and apoptosis induced by Abeta(1-42), H2O2 and KA compared with wild-type neuronal cultures. The results are consonant with the hypothesis that Abeta(1-42)-associated oxidative stress and increased vulnerability to oxidative stress may contribute significantly to neuronal apoptosis and death in familial early onset AD.

Aldehydes↗

PubMed2006

Pin1 in Alzheimer's disease.

Proteolytic processing and phosphorylation of amyloid precursor protein (APP), and hyperphosphorylation of tau protein, have been shown to be increased in Alzheimer's disease (AD) brains, leading to increased production of beta-amyloid (Abeta) peptides and neurofibrillary tangles, respectively. These observations suggest that phosphorylation events are critical to the understanding of the pathogenesis and treatment of this devastating disease. Pin-1, one of the peptidyl-prolyl isomerases (PPIase), catalyzes the isomerization of the peptide bond between pSer/Thr-Pro in proteins, thereby regulating their biological functions which include protein assembly, folding, intracellular transport, intracellular signaling, transcription, cell cycle progression and apoptosis. A number of previous studies have shown that Pin1 is co-localized with phosphorylated tau in AD brain, and shows an inverse relationship to the expression of tau. Pin1 protects neurons under in vitro conditions. Moreover, recent studies demonstrate that APP is a target for Pin1 and thus, in Abeta production. Furthermore, Pin1 was found to be oxidatively modified and to have reduced activity in the hippocampus in mild cognitive impairment (MCI) and AD. Because of the diverse functions of Pin1, and the discovery that this protein is one of the oxidized proteins common to both MCI and AD brain, the question arises as to whether Pin1 is one of the driving forces for the initiation or progression of AD pathogenesis, finally leading to neurodegeneration and neuronal apoptosis. In the present review, we discuss the role of Pin1 with respect to Alzheimer's disease.

Alzheimer Disease↗

PubMed2006

Increase in Mrp1 expression and 4-hydroxy-2-nonenal adduction in heart tissue of Adriamycin-treated C57BL/6 mice.

Multidrug resistance-associated protein 1 (MRP1) mediates the ATP-dependent efflux of endobiotics and xenobiotics, including estradiol 17-(beta-d-glucuronide), leukotriene C(4), and the reduced glutathione conjugate of 4-hydroxy-2-nonenal (HNE), a highly reactive product of lipid peroxidation. Adriamycin is an effective cancer chemotherapeutic drug whose use is limited by cardiotoxicity. Adriamycin induces oxidative stress and production of HNE in cardiac tissue, which may contribute to cardiomyopathy. We investigated the role of Mrp1 in Adriamycin-induced oxidative stress in cardiac tissue. Mice were treated with Adriamycin (20 mg/kg, i.p.), and heart homogenate and sarcolemma membranes were assayed for Mrp1 expression and ATP-dependent transport activity. Expression of Mrp1 was increased at 6 and 24 hours after Adriamycin treatment compared with saline treatment. HNE-adducted proteins were significantly increased (P < 0.001) in the homogenates at 6 hours after Adriamycin treatment and accumulated further with time; HNE adduction of a 190-kDa protein was evident 3 days after Adriamycin treatment. Mrp1 was localized predominately in sarcolemma as shown by confocal and Western blot analysis. Sarcolemma membrane vesicles transported leukotriene C(4) with a K(m) and V(max) of 51.8 nmol/L and 94.1 pmol/min/mg, respectively, and MK571 (10 micromol/L) inhibited the transport activity by 65%. Exposure of HEK(Mrp1) membranes to HNE (10 micromol/L) significantly decreased the V(max) for estradiol 17-(beta-d-glucuronide) transport by 50%. These results show that expression of Mrp1 in the mouse heart is localized predominantly in sarcolemma. Adriamycin treatment increased Mrp1 expression and HNE adduction of Mrp1. Cardiac Mrp1 may play a role in protecting the heart from Adriamycin-induced cardiomyopathy by effluxing HNE conjugates.

Aldehydes↗

PubMed2006

Redox proteomics identification of oxidatively modified brain proteins in inherited Alzheimer's disease: an initial assessment.

OBJECTIVE: To identify oxidatively modified proteins in brains of persons with inherited Alzheimer's disease. METHODS: Redox proteomics was used to identify oxidatively modified brain proteins in persons with mutations in the genes for presenilin-1 (PS-1). RESULTS: An initial redox proteomics assessment of oxidatively modified proteins from brains of individuals with PS-1 mutations was performed. These PS1 mutations, Q222H and M233T, are completely penetrant causing early-onset familial AD as previously reported in these Australian families. We show that oxidative modifications of ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), gamma-enolase, actin, and dimethylarginine dimethylaminohydrolase 1 (DMDMAH-1) are present in the brain of familial AD subjects. CONCLUSIONS: These initial results suggest that oxidatively modified proteins are important common features in both familial and sporadic AD.

Actins↗

PubMed2005

In vivo protection of synaptosomes by ferulic acid ethyl ester (FAEE) from oxidative stress mediated by 2,2-azobis(2-amidino-propane)dihydrochloride (AAPH) or Fe(2+)/H(2)O(2): insight into mechanisms of neuroprotection and relevance to oxidative stress-related neurodegenerative disorders.

Ferulic acid ethyl ester (FAEE) is an ester derivative of ferulic acid, the latter known for its anti-inflammatory and antioxidant properties. Previous studies from our laboratory have shown that ferulic acid protects synaptosomal membrane system and neuronal cell culture systems against hydroxyl and peroxyl radical oxidation. FAEE is lipophilic and is able to penetrate lipid bilayer. Previous studies reported that FAEE reduces Alzheimer's amyloid beta peptide Abeta(1-42)-induced oxidative stress and cytotoxicity in neuronal cell culture by direct radical scavenging and by inducing certain antioxidant proteins. In the present study we tested the hypothesis that FAEE would provide neuroprotection against free radical oxidative stress in vivo. Synaptosomes were isolated from the gerbils that were previously injected intraperitoneally (i.p.) with FAEE or DMSO and were treated with oxidants, Fe(2+)/H(2)O(2) or 2,2-azobis(2-amidino-propane)dihydrochloride (AAPH). Synaptosomes isolated from the gerbil previously injected i.p. with FAEE and treated with Fe(2+)/H(2)O(2) and AAPH showed significant reduction in reactive oxygen species (ROS), levels of protein carbonyl, protein bound 4-hydroxynonenal (HNE, a lipid peroxidation product), and 3-nitrotyrosine (3-NT, another marker of protein oxidation formed by reaction of tyrosine residues with peroxynitrite) compared to Fe(2+)/H(2)O(2) or AAPH induced oxidative stress in synapotosomes isolated from the brain of gerbils that were previously injected with DMSO. The synaptosomes isolated from gerbil pre-injected with FAEE and subsequently treated with AAPH or Fe(2+)/H(2)O(2) showed induction of heme oxygenase (HO-1) and heat shock protein 70 (HSP-70) but reduced inducible nitric oxide synthase (iNOS) levels. These results are discussed with reference to potential use of this lipophilic antioxidant phenolic compound in the treatment of oxidative stress-related neurodegenerative disorders.

Aldehydes↗

PubMed2005

Identification of nitrated proteins in Alzheimer's disease brain using a redox proteomics approach.

Nitric oxide (NO) has been implicated in the pathophysiology of a number of neurodegenerative diseases including Alzheimer's disease (AD). In the present study, using a proteomics approach, we identified enolase, glyceraldehyde-3-phosphate dehydrogenase, ATP synthase alpha chain, carbonic anhydrase-II, and voltage-dependent anion channel-protein as the targets of nitration in AD hippocampus, a region that shows a extensive deposition of amyloid beta-peptide, compared with the age-matched control brains. Immunoprecipitation and Western blotting techniques were used to validate the correct identification of these proteins. Our results are discussed in context of the role of oxidative stress as one of the important mechanisms of neurodegeneration in AD.

ATP Synthetase Complexes↗

PubMed2005

HIV-dementia, Tat-induced oxidative stress, and antioxidant therapeutic considerations.

Oxidative stress is thought to play a role in the onset of dementia. HIV-dementia has recently been demonstrated to be associated with oxidative stress as indexed by increased protein and lipid peroxidation in the brain and cerebrospinal fluid compared to HIV non-demented patients. The HIV protein Tat induces neurotoxicity, and, more recently, Tat was found to induce oxidative stress directly and indirectly. The role of Tat in HIV-dementia and possible therapeutic strategies involving endogenous and exogenous antioxidants are discussed.

AIDS Dementia Complex↗

PubMed2005

Redox proteomics identification of oxidized proteins in Alzheimer's disease hippocampus and cerebellum: an approach to understand pathological and biochemical alterations in AD.

Alzheimer's disease (AD) is characterized by the presence of neurofibrillary tangles, senile plaques and loss of synapses. There is accumulating evidence that oxidative stress plays an important role in AD pathophysiology. Previous redox proteomics studies from our laboratory on AD inferior parietal lobule led to the identification of oxidatively modified proteins that were consistent with biochemical or pathological alterations in AD. The present study was focused on the identification of specific targets of protein oxidation in AD and control hippocampus and cerebellum using a redox proteomics approach. In AD hippocampus, peptidyl prolyl cis-trans isomerase, phosphoglycerate mutase 1, ubiquitin carboxyl terminal hydrolase 1, dihydropyrimidinase related protein-2 (DRP-2), carbonic anhydrase II, triose phosphate isomerase, alpha-enolase, and gamma-SNAP were identified as significantly oxidized protein with reduced enzyme activities relative to control hippocampus. In addition, no significant excessively oxidized protein spots were identified in cerebellum compared to control, consistent with the lack of pathology in this brain region in AD. The identification of oxidatively modified proteins in AD hippocampus was verified by immunochemical means. The identification of common oxidized proteins in different brain regions of AD brain suggests a potential role for these oxidized proteins and thereby oxidative stress in the pathogenesis of Alzheimer's disease.

Aged↗

PubMed2005

Acetylcarnitine and cellular stress response: roles in nutritional redox homeostasis and regulation of longevity genes.

Aging is associated with a reduced ability to cope with physiological challenges. Although the mechanisms underlying age-related alterations in stress tolerance are not well defined, many studies support the validity of the oxidative stress hypothesis, which suggests that lowered functional capacity in aged organisms is the result of an increased generation of reactive oxygen and nitrogen species. Increased production of oxidants in vivo can cause damage to intracellular macromolecules, which can translate into oxidative injury, impaired function and cell death in vulnerable tissues such as the brain. To survive different types of injuries, brain cells have evolved networks of responses, which detect and control diverse forms of stress. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of several genes termed vitagenes. Among these, heat shock proteins form a highly conserved system responsible for the preservation and repair of the correct protein conformation. The heat shock response contributes to establishing a cytoprotective state in a wide variety of human diseases, including inflammation, cancer, aging and neurodegenerative disorders. Given the broad cytoprotective properties of the heat shock response, there is now a strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. Acetylcarnitine is proposed as a therapeutic agent for several neurodegenerative disorders, and there is now evidence that it may play a critical role as modulator of cellular stress response in health and disease states. In the present review, we first discuss the role of nutrition in carnitine metabolism, followed by a discussion of carnitine and acetyl-l-carnitine in mitochondrial dysfunction, in aging, and in age-related disorders. We then review the evidence for the role of acetylcarnitine in modulating redox-dependent mechanisms leading to up-regulation of vitagenes in brain, and we also discuss new approaches for investigating the mechanisms of lifetime survival and longevity.

Acetylcarnitine↗

PubMed2005

Redox proteomics identification of oxidatively modified proteins in Alzheimer's disease brain and in vivo and in vitro models of AD centered around Abeta(1-42).

Alzheimer's disease is a progressive neurodegenerative disease associated with loss of memory and cognition. One hallmark of AD is the accumulation of amyloid beta-peptide (Abeta), which invokes a cascade of oxidative damage to neurons that can eventually result in neuronal death. Several markers of oxidative stress have been identified in AD brain, thus providing greater understanding into potential mechanisms involved in the disease pathogenesis and progression. In the present article, we review the application of redox proteomics to the identification of oxidized proteins in AD brain and also our recent findings on amyloid beta-peptide (Abeta)-associated in vivo and in vitro models of AD. Our redox proteomics approach has made possible the identification of specifically oxidized proteins in Alzheimer's disease (AD) brain, providing for the first time evidence on how oxidative stress plays a crucial role in AD-related neurodegeneration. The information obtained has great potential to aid in determining the molecular pathogenesis in and detecting disease markers of AD, as well as identifying potential targets for drug therapy in AD. Application of redox proteomics to study cellular events, especially related to disease dysfunction, may provide an efficient tool to understand the main mechanisms involved in the pathogenesis and progression of oxidative stress-related neurodegenerative disorders.

Alzheimer Disease↗

PubMed2005

Proteomic identification of proteins specifically oxidized in Caenorhabditis elegans expressing human Abeta(1-42): implications for Alzheimer's disease.

Protein oxidation has been shown to lead to loss of protein function, increased protein aggregation, decreased protein turnover, decreased membrane fluidity, altered cellular redox poteintial, loss of Ca2+ homeostaisis, and cell death. There is increasing evidence that protein oxidation is involved in the pathogenesis of Alzheimer's disease and amyloid beta-peptide (1-42) has been implicated as a mediator of oxidative stress in AD. However, the specific implications of the oxidation induced by Abeta(1-42) on the neurodegeneration evident in AD are unknown. In this study, we used proteomic techniques to identify specific targets of oxidation in transgenic Caenorhabditis elegans (C. elegans) expressing human Abeta(1-42). We identified 16 oxidized proteins involved in energy metabolism, proteasome function, and scavenging of oxidants that are more oxidized compared to control lines. These results are discussed with reference to Alzheimer's disease.

Amyloid beta-Peptides↗

PubMed2005

Proteomic identification of less oxidized brain proteins in aged senescence-accelerated mice following administration of antisense oligonucleotide directed at the Abeta region of amyloid precursor protein.

Amyloid beta-peptide (Abeta) is the major constituent of senile plaques, a pathological hallmark of Alzheimer's disease (AD) brain. It is generally accepted that Abeta plays a central role in the pathophysiology of AD. Abeta is released from cells under entirely normal cellular conditions during the internalization and endosomal processing of amyloid precursor protein (APP). However, accumulation of Abeta can induce neurotoxicity. Our previous reports showed that decreasing the production of Abeta by giving an intracerebroventricular injection of a 42-mer phosphorothiolated antisense oligonucleotide (AO) directed at the Abeta region of the APP gene reduces lipid peroxidation and protein oxidation and improves cognitive deficits in aged senescence-accelerated mice prone 8 (SAMP8) mice. In order to investigate how Abeta level reduction improves learning and memory performance of SAMP8 mice through reduction of oxidative stress in brains, we used proteomics to identify the proteins that are less oxidized in 12-month-old SAMP8 mice brains treated with AO against the Abeta region of APP (12 mA) compared to that of the age-control SAMP8 mice. We found that the specific protein carbonyl levels of aldoase 3 (Aldo3), coronin 1a (Coro1a) and peroxiredoxin 2 (Prdx2) are significantly decreased in the brains of 12 mA SAMP8 mice compared to the age-controlled SAMP8 treated with random AO (12 mR). We also found that the expression level of alpha-ATP synthase (Atp5a1) was significantly decreased, whereas the expression of profilin 2 (Pro-2) was significantly increased in brains from 12 mA SAMP8 mice. Our results suggest that decreasing Abeta levels in aged brain in aged accelerated mice may contribute to the mechanism of restoring the learning and memory improvement in aged SAMP8 mice and may provide insight into the role of Abeta in the memory and cognitive deficits in AD.

Acetaldehyde↗

PubMed2005

The senescence-accelerated prone mouse (SAMP8): a model of age-related cognitive decline with relevance to alterations of the gene expression and protein abnormalities in Alzheimer's disease.

The senescence-accelerated mouse (SAM) is an accelerated aging model that was established through phenotypic selection from a common genetic pool of AKR/J strain of mice. The SAM model was established in 1981, including nine major senescence-accelerated mouse prone (SAMP) substrains and three major senescence-accelerated mouse resistant (SAMR) substrains, each of which exhibits characteristic disorders. Recently, SAMP8 have drawn attention in gerontological research due to its characteristic learning and memory deficits at old age. Many recent reports provide insight into mechanisms of the cognitive impairment and pathological changes in SAMP8. Therefore, this mini review examines the recent findings of SAMP8 mice abnormalities at the gene and protein levels. The genes and proteins described in this review are functionally categorized into neuroprotection, signal transduction, protein folding/degradation, cytoskeleton/transport, immune response and reactive oxygen species (ROS) production. All of these processes are involved in learning and memory. Although these studies provide insight into the mechanisms that contribute to the learning and memory decline in aged SAMP8 mice, higher throughput techniques of proteomics and genomics are necessary to study the alterations of gene expression and protein abnormalities in SAMP8 mice brain in order to more completely understand the central nervous system dysfunction in this mouse model. The SAMP8 is a good animal model to investigate the fundamental mechanisms of age-related learning and memory deficits at the gene and protein levels.

Aging↗