Roles of ApoE4 on the Pathogenesis in Alzheimer's Disease and the Potential Therapeutic Approaches.

The Apolipoprotein E ε4 (ApoE ε4) allele, encoding ApoE4, is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). Emerging epidemiological evidence indicated that ApoE4 contributes to AD through influencing ß-amyloid (Aß) deposition and clearance. However, the molecular mechanisms of ApoE4 involved in AD pathogenesis remains unclear. Here, we introduced the structure and functions of ApoE isoforms, and then we reviewed the potential mechanisms of ApoE4 in the AD pathogenesis, including the effect of ApoE4 on Aß pathology, and tau phosphorylation, oxidative stress; synaptic function, cholesterol transport, and mitochondrial dysfunction; sleep disturbances and cerebrovascular integrity in the AD brains. Furthermore, we discussed the available strategies for AD treatments that target to ApoE4. In general, this review overviews the potential roles of ApoE4 in the AD development and suggests some therapeutic approaches for AD. ApoE4 is genetic risk of AD. ApoE4 is involved in the AD pathogenesis. Aß deposition, NFT, oxidative stress, abnormal cholesterol, mitochondrial dysfunction and neuroinflammation could be observed in the brains with ApoE4. Targeting the interaction of ApoE4 with the AD pathology is available strategy for AD treatments.

Sleep-Wake Disorders in Alzheimer's Disease: A Review.

Alzheimer's disease (AD) is a multifactorial disease, and it has become a serious health problem in the world. Senile plaques (SPs) and neurofibrillary tangles (NFTs) are two main pathological characters of AD. SP mainly consists of aggregated ß-amyloid (Aß), and NFT is formed by hyperphosphorylated tau protein. Sleep-wake disorders are prevalent in AD patients; however, the links and mechanisms of sleep-wake disorders on the AD pathogenesis remain to be investigated. Here, we referred to the sleep-wake disorders and reviewed some evidence to demonstrate the relationship between sleep-wake disorders and the pathogenesis of AD. On one hand, the sleep-wake disorders may lead to the increase of Aß production and the decrease of Aß clearance, the spreading of tau pathology, as well as oxidative stress and inflammation. On the other hand, the ApoE4 allele, a risk gene for AD, was reported to participate in sleep-wake disorders. Furthermore, some neurotransmitters, such as acetylcholine, glutamate, serotonin, melatonin, and orexins, and their receptors were suggested to be involved in AD development and sleep-wake disorders. We discussed and suggested some possible therapeutic strategies for AD treatment based on the view of sleep regulation. In general, this review explored different views to find novel targets of diagnosis and therapy for AD.

Curcumin Inhibits Cell Damage and Apoptosis Caused by Thapsigargin-Induced Endoplasmic Reticulum Stress Involving the Recovery of Mitochondrial Function Mediated by Mitofusin-2.

Endoplasmic reticulum stress (ERS) and mitochondrial dysfunction have been suggested to relate with the pathology of Alzheimer's disease (AD). However, their cross-talk is needed to investigate further. Mitofusin-2 (Mfn2) is a member of mitochondria-associated membrane (MAM), which connects endoplasmic reticulum (ER) and mitochondria. This study investigated the protective effect of curcumin on thapsigargin (TG)-induced ERS and cell apoptosis and the role of Mfn2 on mitochondrial dysfunction. The cell viability of SH-SY5Y cells was decreased and cell damage and apoptosis were increased in a concentration-dependent manner when cells were treated with TG. TG upregulated the protein levels of GRP78, pSer981-PERK, and pSer51-eIF2α. Curcumin attenuated TG-induced damage on cell viability and apoptosis and downregulated the protein levels of GRP78, pSer981-PERK, and pSer51-eIF2α. TG caused the increases in intracellular reactive oxygen species (ROS) and in the protein levels of pSer40-Nrf2 and hemoglobin oxygenase 1 (HO-1). Curcumin decreased the TG-induced intracellular ROS but did not alter the protein levels of pSer40-Nrf2 and HO-1. TG resulted in the upregulation on Mfn2 expression and mitochondrial spare respiratory capacity but the downregulation on mitochondrial basal respiration and ATP production. Curcumin attenuated the TG-induced Mfn2 expression and mitochondrial stress. When Mfn2 was silenced by shRNA interference, curcumin failed to recovery the TG-damaged mitochondrial function. In general, the TG-induced ERS trigged mitochondrial dysfunction and cell apoptosis. Curcumin attenuates TG-induced ERS and the cell damage and apoptosis. Mfn2 is required for curcumin's protection against the TG-induced damage on mitochondrial functions.

Phosphorylation and Glycosylation of Amyloid-ß Protein Precursor: The Relationship to Trafficking and Cleavage in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder in the central nervous system, and this disease is characterized by extracellular senile plaques and intracellular neurofibrillary tangles. Amyloid-ß (Aß) peptide is the main constituent of senile plaques, and this peptide is derived from the amyloid-ß protein precursor (AßPP) through the successive cleaving by ß-site AßPP-cleavage enzyme 1 (BACE1) and γ-secretase. AßPP undergoes the progress of post-translational modifications, such as phosphorylation and glycosylation, which might affect the trafficking and the cleavage of AßPP. In the recent years, about 10 phosphorylation sites of AßPP were identified, and they play complex roles in glycosylation modification and cleavage of AßPP. In this article, we introduced the transport and the cleavage pathways of AßPP, then summarized the phosphorylation and glycosylation sites of AßPP, and further discussed the links and relationship between phosphorylation and glycosylation on the pathways of AßPP trafficking and cleavage in order to provide theoretical basis for AD research.

Independent and Correlated Role of Apolipoprotein E ɛ4 Genotype and Herpes Simplex Virus Type 1 in Alzheimer's Disease.

The ɛ4 allele of the Apolipoprotein E (APOE) gene in individuals infected by Herpes simplex virus type 1 (HSV-1) has been demonstrated to be a risk factor in Alzheimer's disease (AD). APOE-ɛ4 reduces the levels of neuronal cholesterol, interferes with the transportation of cholesterol, impairs repair of synapses, decreases the clearance of neurotoxic peptide amyloid-ß (Aß), and promotes the deposition of amyloid plaque, and eventually may cause development of AD. HSV-1 enters host cells and can infect the olfactory system, trigeminal ganglia, entorhinal cortex, and hippocampus, and may cause AD-like pathological changes. The lifecycle of HSV-1 goes through a long latent phase. HSV-1 induces neurotropic cytokine expression with pro-inflammatory action and inhibits antiviral cytokine production in AD. It should be noted that interferons display antiviral activity in HSV-1-infected AD patients. Reactivated HSV-1 is associated with infectious burden in cognitive decline and AD. Finally, HSV-1 DNA has been confirmed as present in human brains and is associated with APOEɛ4 in AD. HSV-1 and APOEɛ4 increase the risk of AD and relate to abnormal autophagy, higher concentrations of HSV-1 DNA in AD, and formation of Aß plaques and neurofibrillary tangles.

Inhibitory effects of curcumin on H2O2-induced cell damage and APP expression and processing in SH-SY5Y cells transfected with APP gene with Swedish mutation.

Alzheimer's disease (AD) is a neurodegenerative disorder, and the pathological mechanism of the disease is still far to understand. According to the amyloid cascade hypothesis in AD, Amyloid-ß (Aß) is considered as a key substance that contributes AD development. Aß is a ß-cleaving product from Amyloid-ß protein precursor (APP). Mutations of APP including APPKM670/671670NL (Swedish mutation) result in Aß overproduction and the development of early-onset familial AD. Increase of oxidative stress and damage also occurs in early stage of AD. In this study, we used a SH-SY5Y cell line that stably expresses APP gene with Swedish mutation (SH-SY5Y-APPswe), and the inhibitory effects of curcumin on H2O2-induced cell damage and APP processing were investigated. Cells were treated with curcumin (0 ~ 5 µM) for 4 h before hydrogen peroxide (H2O2). Cell growth was detected with CCK-8 assay, and cell damage was determined through the evaluation of release of lactate dehydrogenase (LDH) from the cytosol to the culture medium and the morphological change of nucleus. The ability of mitochondrial stress and the depolarization of mitochondrial membrane potential were assayed through the measuring the oxygen consumption rate (OCR) and the green/red fluorescence ratio of JC-1 dye respectively. The protein levels of APP, sAPPα, sAPPß, and BACE1 were analyzed with Western blot assay. Aß production was measured with enzyme-linked immunosorbent assay (ELISA). The results indicated that curcumin inhibits H2O2-induced decrease of cell growth and cell damage. Curcumin attenuates H2O2-induced damage on the ability to mitochondrial oxidative phosphorylation and membrane potential. Curcumin inhibits H2O2-induced increase of APP cleavage through ß-cleavage pathway and of intracellular Aß production. These results imply that curcumin can be used to treat AD through inhibiting oxidative damage-induced APP ß-cleavage and intracellular Aß generation.

Regulation of AßPP Glycosylation Modification and Roles of Glycosylation on AßPP Cleavage in Alzheimer's Disease.

The presence of senile plaques in the gray matter of the brain is one of the major pathologic features of Alzheimer's disease (AD), and amyloid-ß (Aß) is the main component of extracellular deposits of the senile plaques. Aß derives from amyloid-ß precursor protein (AßPP) cleaved by ß-secretase (BACE1) and γ-secretase, and the abnormal cleavage of AßPP is an important event leading to overproduction and aggregation of Aß species. After translation, AßPP undergoes post-translational modifications (PTMs) including glycosylation and phosphorylation in the endoplasmic reticulum (ER) and Golgi apparatus, and these modifications play an important role in regulating the cleavage of this protein. In this Review, we summarize research progress on the modification of glycosylation, especially O-GlcNAcylation and mucin-type O-linked glycosylation (also known as O-GalNAcylation), on the regulation of AßPP cleavage and on the influence of AßPP's glycosylation in the pathogenesis of AD.

Modulation of AßPP and GSK3ß by Endoplasmic Reticulum Stress and Involvement in Alzheimer's Disease.

Alzheimer's disease (AD) is a dementia disease with neuronal loss and synaptic impairment. This impairment is caused, at least partly, by the generation of two main AD hallmarks, namely the hyperphosphorylated tau protein comprising neurofibrillary tangles and senile plaques containing amyloid-ß (Aß) peptides. The amyloid-ß protein precursor (AßPP) and glycogen synthase kinase-3ß (GSK3ß) are two main proteins associated with AD and are closely correlated with these hallmarks. Recently, both of the proteins were reported to be modulated by endoplasmic reticulum stress (ERS) and are involved in the pathogenesis of AD. The mechanism of ERS plus the modulation of AßPP processing and GSK3ß activity by ERS in AD are summarized and explored in this review.

Antioxidative and Neuroprotective Effects of Curcumin in an Alzheimer's Disease Rat Model Co-Treated with Intracerebroventricular Streptozotocin and Subcutaneous D-Galactose.

Epidemiological data imply links between the increasing incidences of Alzheimer's disease (AD) and type 2 diabetes mellitus. In this study, an AD rat model was established by combining treatments with intracerebroventricular streptozotocin (icv-STZ) and subcutaneous D-galactose, and the effects of curcumin on depressing AD-like symptoms were investigated. In the AD model group, rats were treated with icv-STZ in each hippocampus with 3.0 mg/kg of bodyweight once and then were subcutaneously injected with D-galactose daily (125 mg/kg of bodyweight) for 7 weeks. In the curcumin-protective group, after icv-STZ treatment, rats were treated with D-galactose (the same as in the AD model group) and intraperitoneally injected with curcumin daily (10 mg/kg of bodyweight) for 7 weeks. Vehicle-treated rats were treated as control. Compared with the vehicle control, the amount of protein carbonylation and glutathione in liver, as well as malondialdehyde in serum, were upregulated but glutathione peroxidase activity in blood was downregulated in the AD model group. The shuttle index and locomotor activity of rats in the AD model group were decreased compared with the vehicle control group. Furthermore, AD model rats showed neuronal damage and neuron loss with formation of amyloid-like substances and neurofibrillary tangles, and the levels of both ß-cleavage of AßPP and phosphorylation of tau (Ser396) were significantly increased compared with the vehicle control group. Notably, compared with the AD model group, oxidative stress was decreased and the abilities of active avoidance and locomotor activity were improved, as well as attenuated neurodegeneration, in the curcumin-protective group. These results imply the applications of this animal model for AD research and of curcumin in the treatment of AD.

Roles of O-GlcNAcylation on amyloid-ß precursor protein processing, tau phosphorylation, and hippocampal synapses dysfunction in Alzheimer's disease.

Alzheimer disease (AD), a central nervous system degenerative disease, is characterized by abnormal deposition of amyloid-ß peptide (Aß), neurofibrillary tangles formed by hyperphosphorylated tau and synaptic loss. It is widely accepted that Aß is the chief culprit of AD. Aß peptide is the cleavage product of amyloid-ß precursor protein (APP). Recently, more attention has been paid to O-linked ß-N-acetylglucosaminylation (O-GlcNAcylation) modification of protein. O-GlcNAcylation plays a significant role in hippocampal synaptic function. Abated O-GlcNAcylation might be a modulator in progression of AD through regulating activity of pertinent enzymes and factors. Evidence suggests that enhanced O-GlcNAcylation interacts with tau phosphorylation and prevents brain from tau and Aß-induced impairment. Here, we review the roles of O-GlcNAcylation in APP cleavage, tau phosphorylation and hippocampal synapses function.

Protection of curcumin against amyloid-ß-induced cell damage and death involves the prevention from NMDA receptor-mediated intracellular Ca2+ elevation.

Alzheimer's disease (AD) is one of the common neurodegenerative diseases and amyloid-ß (Aß) is thought to be a key molecule contributing to AD pathology. Recently, curcumin is supposed to be beneficial to AD treatment. This study investigates the inhibitory effects of curcumin on Aß-induced cell damage and death involving NMDA receptor-mediated intracellular Ca(2+) elevation in human neuroblastoma SH-SY5Y cells. Cells were impaired significantly in Aß-damaged group compared with the control group, and cell viability was decreased while the released LDH from the cytosol was increased. Curcumin promotes cell growth and decreases cell impairment induced by Aß. Curcmin attenuates Aß-induced elevation of the ratio of cellular glutamate/γ-aminobutyric acid (GABA) with a concentration-dependent manner. Curcumin inhibits Aß-induced increase of cellular Ca(2+) and depresses Aß-induced phosphorylations of both NMDA receptor and cyclic AMP response element-binding protein (CREB) and activating transcription factor 1 (ATF-1). These results indicated that curcumin inhibits Aß-induced neuronal damage and cell death involving the prevention from intracellular Ca(2+) elevation mediated by the NMDA receptor.

Chitooligosaccharides attenuate Cu2+-induced cellular oxidative damage and cell apoptosis involving Nrf2 activation.

Alzheimer's disease (AD) is one of the common neurodegenerative diseases. Increase of labile copper pool plays an important role in the pathogenesis of AD. Nrf2(NF-E2-related factor-2)-ARE (antioxidant response element) signaling is an important intracellular manner to defend against oxidative stress. In this study, we used SH-SY5Y cells as a model of neuron to test the effect of chitooligosaccharides (COSs) on Cu(2+)-induced oxidative damage. SH-SY5Y cells were treated with different concentrations of COSs (100-800 mg/L) before incubated with Cu(2+). Cell viability and cell damage and apoptosis were assessed. Both extracellular H(2)O(2) and intracellular ROS were measured and the relative levels of Nrf2, phosphorylated Nrf2, and HO-1 were analyzed by Western blotting, and further HO-1 mRNA was relatively quantified by real-time quantitative PCR. The results indicated that Cu(2+)-induced decrease of cell viability and increase of LDH release. In cell-free solution, COSs alone or with Cu(2+) cannot scavenge O(2)(-); however, COSs downregulate the levels of cellular oxidative stress and activated Caspase-3 induced by Cu(2+). Further, the levels of pSer40-Nrf2 protein and both the transcription and the translation of HO-1 gene are dramatically increased in COSs-protective group compared with Cu(2+) damage group. Therefore, these results indicate that Nrf2 activation might be involved in the protection of COSs against Cu(2+)-induced cellular oxidative damage. COSs contribute to the attenuation of oxidative damage and could be used as a nutritional agent for AD treatment.

Endoplasmic reticulum stress as a novel neuronal mediator in Alzheimer's disease.

Alzheimer's disease (AD) is one of the most common types of progressive dementias. The typical neuropathological changes in AD include extracellular senile plaques, intracellular neurofibrillary tangles, and loss of neurons. The pathogenetic mechanism of this disease is not comprehensively understood yet. Recently, endoplasmic reticulum stress (ER stress) has been considered as a potential event involved in AD development. Some AD-related factors, such as misfolded protein and Ca(2+) depletion, could disrupt the homeostasis of ER lumen. In AD, the aggregated amyloid-beta peptide (Abeta) could induce ER stress in an assembly dependent way. The presenilin has been identified as a Ca(2+) channel. Mutations of presenilin could change the balance of Ca(2+) in ER lumen and thus disrupts the ER homeostasis. Furthermore, the ER stress could lead to cellular disorders like inflammation. Through activating the expression of inflammatory factors, ER stress triggers inflammatory response in AD pathology. Herein, we reviewed the recent progress of ER stress-induced unfolded protein response (UPR) and the roles of ER stress in AD pathological process.

Relationship between amyloid-beta and the ubiquitin-proteasome system in Alzheimer's disease.

Amyloid-beta (Abeta) peptide is the original causative factor of Alzheimer's disease (AD) according to the amyloid cascade hypothesis. The ubiquitin-proteasome system (UPS), the major intracellular protein quality control system in eukaryotic cells, is related to AD pathogenesis. There is growing evidence showing that there is a tight relationship between Abeta and UPS and this relationship plays an important role in AD pathogenesis. This article reviews the relationship between Abeta and the UPS in terms of the following three aspects: the interaction of the two factors, the ubiquitinating process of Abeta, and impact of dysfunctional UPS on Abeta production. The impairment in the UPS in AD could affect the degradation of Abeta and lead to an abnormal accumulation of Abeta. At the same time, Abeta inhibits the proteasomal activity and subsequently leads to impairment of multivesicular bodies (MVB) sorting pathway, forming an interacting relationship between Abeta and UPS. Mutant ubiquitin (Ub) and ubiquitin-like (UBL) ubiquilin-1 are related to Abeta accumulation. Meanwhile E2 conjugating enzymes, E3 ligases, and de-ubiquitinating enzymes, all of which function in the ubiquitination process, play a pivotal role in the proteasomal degradation of Abeta. Ubiquitin-proteasome system has an immense impact on the amyloidogenic pathway of amyloid precursor protein (APP) processing that generates Abeta. Upregulation in proteasomal degradation of BACE1 and components of gamma-secretase leads to decreased Abeta accumulation. A deep look into the mechanism underlying the interplay between Abeta and UPS may provide alternative therapeutic targets and lead to new drugs and therapies.

Curcumin attenuates amyloid-ß-induced tau hyperphosphorylation in human neuroblastoma SH-SY5Y cells involving PTEN/Akt/GSK-3ß signaling pathway.

Accumulated amyloid-ß peptide (Aß) and hyperphosphorylated tau proteins are two hallmarks of Alzheimer's disease (AD). Increasing evidence suggests that Aß induces tau hyperphosphorylation in AD pathology, but the signaling pathway is not completely understood. Inhibiting Aß-induced cellular signaling is beneficent to AD treatment. In this study, cellular signaling of tau phosphorylation induced by Aß and the inhibiting effects of curcumin on this signaling were investigated on human neuroblastoma SH-SY5Y cells. The results indicated that curcumin inhibits Aß-induced tau phosphorylation at Thr231 and Ser396, over-expression of HDAC6, and decrease in phosphorylation of glycogen synthase kinase-3ß (GSK-3ß) at Ser9. However, the protective effect of curcumin on dephosphorylation of GSK-3ß induced by Aß is not directly related to cellular oxidative stress. Curcumin depresses Aß-induced down-regulation of phosphorylations of Akt at Thr308 and Ser473 and 3-phosphoinositide-dependent protein kinase 1 at Ser241, implying that second message PIP3 involves curcumin-protective cell signaling. Furthermore, insulin receptor/phosphatidyl inositol 3-kinase pathway, as a regulatory signaling of second message PIP3, does not participate in Aß-induced deactivation of Akt (dephosphorylation at Thr308 and Ser473). However, Aß results in over-expression of Phosphatase and tensin homolog (PTEN), a negative regulator of PIP3. Curcumin depresses Aß-induced up-regulation of PTEN induced by Aß. These results imply that curcumin inhibits Aß-induced tau hyperphosphorylation involving PTEN/Akt/GSK-3ß pathway.

Mitochondrial dysfunction and cellular metabolic deficiency in Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder. The pathology of AD includes amyloid-ß (Aß) deposits in neuritic plaques and neurofibrillary tangles composed of hyperphosphorylated tau, as well as neuronal loss in specific brain regions. Increasing epidemiological and functional neuroimaging evidence indicates that global and regional disruptions in brain metabolism are involved in the pathogenesis of this disease. Aß precursor protein is cleaved to produce both extracellular and intracellular Aß, accumulation of which might interfere with the homeostasis of cellular metabolism. Mitochondria are highly dynamic organelles that not only supply the main energy to the cell but also regulate apoptosis. Mitochondrial dysfunction might contribute to Aß neurotoxicity. In this review, we summarize the pathways of Aß generation and its potential neurotoxic effects on cellular metabolism and mitochondrial dysfunction.

Curcumin-mediated neuroprotection against amyloid-ß-induced mitochondrial dysfunction involves the inhibition of GSK-3ß.

The deposition of amyloid-ß (Aß) peptides in senile plaques is one of pathological hallmarks of Alzheimer's disease (AD). Mitochondrial dysfunction is an early event of cell apoptosis. Increasing evidence indicates that Aß induces neuronal apoptosis through mitochondrial dysfunction. Curcumin, an anti-oxidative component of turmeric (Curcuma longa), has shown anti-tumor, anti-inflammatory, and anti-oxidative properties. In this study, we investigated the protective effects of curcumin against mitochondrial dysfunction induced by Aß. Based on the assay results of mitochondrial metabolic markers, we found that curcumin protects human neuroblastoma SH-SY5Y cells against the Aß-induced damage of mitochondrial energy metabolism. Curcumin inhibits Aß-induced mitochondrial depolarization of membrane potential (Δψm) and suppresses mitochondrial apoptosis-related proteins including cytochrome c, caspase-3, and Bax, which are activated by Aß. Aß-induced disturbances of redox state are linked to mitochondrial dysfunction. Curcumin normalizes cellular antioxidant enzymes (including SOD and catalase) in both protein expression and activity and decreases oxidative stress level in Aß-treated cells. Both total GSK-3ß expression and phospho-Ser9 GSK-3ß (pSer9-GSK-3ß) are down-regulated in the cells pre-treated with curcumin. This study demonstrates curcumin-mediated neuroprotection against Aß-induced mitochondrial metabolic deficiency and abnormal alteration of oxidative stress. Inhibition of GSK-3ß is involved in the protection of curcumin against Aß-induced mitochondrial dysfunction.

Protective effects of curcumin on amyloid-ß-induced neuronal oxidative damage.

To investigate the protective effects of curcumin against amyloid-ß (Aß)-induced neuronal damage. Primary rat cortical neurons were cultured with different treatments of Aß and curcumin. Neuronal morphologies, viability and damage were assessed. Neuronal oxidative stress was assessed, including extracellular hydrogen peroxide and intracellular reactive oxygen species. The abilities of curcumin to scavenge free radicals and to inhibit Aß aggregation and ß-sheeted formation are further assessed and discussed. Curcumin preserves cell viability, which is decreased by Aß. The results of changed morphology, released Lactate dehydrogenases and cell viability assays indicate that curcumin protects Aß-induced neuronal damage. Curcumin depresses Aß-induced up-regulation of neuronal oxidative stress. The treatment sequence impacts the protective effect of curcumin on Aß-induced neuronal damage. Curcumin shows a more protective effect on neuronal oxidative damage when curcumin was added into cultured neurons not later than Aß, especially prior to Aß. The abilities of curcumin to scavenge free radicals and to inhibit the formation of ß-sheeted aggregation are both beneficial to depress Aß-induced oxidative damage. Curcumin prevents neurons from Aß-induced oxidative damage, implying the therapeutic usage for the treatment of Alzheimer's disease patients.

Targeting HDACs: a promising therapy for Alzheimer's disease.

Epigenetic modifications like DNA methylation and histone acetylation play an important role in a wide range of brain disorders. Histone deacetylases (HDACs) regulate the homeostasis of histone acetylation. Histone deacetylase inhibitors, which initially were used as anticancer drugs, are recently suggested to act as neuroprotectors by enhancing synaptic plasticity and learning and memory in a wide range of neurodegenerative and psychiatric disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). To reveal the physiological roles of HDACs may provide us with a new perspective to understand the mechanism of AD and to develop selective HDAC inhibitors. This paper focuses on the recent research progresses of HDAC proteins and their inhibitors on the roles of the treatment for AD.

Amyloid-ß protein precursor family members: a review from homology to biological function.

Alzheimer's disease (AD) is one of the most common forms of neurodegenerative disease. Amyloid-ß peptide (Aß) is the most crucial molecule related to the pathological development of AD. Amyloid-ß protein precursor (AßPP) is one of AßPP family members with conserved type I transmembrane. The genetic mutations of AßPP and the abnormity of its post-transcription and proteolytic processing contribute to the elevation of Aß. The accumulation of Aß in senile plaques is believed to be the most important event in AD pathology. Therefore, as a key upstream molecule of Aß, AßPP is related to the AD pathology, but the biological function of AßPP is still not fully clear. AßPP-like proteins are widely expressed in multicellular eukaryotes. AßPP-like homologous genes and proteins are highly conserved in various organisms from invertebrates to mammals. AßPP-like genes undergo similarly pathways of transcription and post-transcription processing, and AßPP-like proteins is proteolyzed by the similar α-cleavage and the ß-cleavage pathways. Based on the homology and the resemble domains, AßPP may play similar roles in organisms. In this article, we reviewed homology and structures of AßPP family members in organisms and further discussed potential biological function in normal and AD brains.