The Trojan horse - neuroinflammatory impact of T cells in neurodegenerative diseases

Neuronal degeneration is a common mechanism of many neurological diseases including Parkinson’s disease (PD), Alzheimer’s disease (AD), and Multiple Sclerosis (MS). While AD and PD are classical neurodegenerative diseases, the primary pathology in MS is driven by autoimmune inflammation, attacking oligodendrocytes and thereby inducing neurodegeneration. In AD and PD, immune cells are also considered to play an important role in the disease progression. While the role of local central nervous system (CNS) innate immune cells is well described, a potential influence of adaptive immune cells in PD and AD is not yet fully understood.Here, we aim to summarize findings concerning adaptive immune cells in PD pathogenesis and compare them to AD and MS. In the first part, we focus on disease-specific alterations of lymphocytes in the circulating blood. Subsequently, we describe what is known about CNS-infiltrated lymphocytes and mechanisms of their infiltration. Finally, we summarize published data and try to understand the mechanisms of how lymphocytes contribute to neurodegeneration in PD, AD, and MS.Lymphocytes are critically involved in the pathogenesis of MS, and clarifying the role of lymphocytes in PD and AD pathogenesis might lead to an identification of a common signature of lymphocytes in neurodegeneration and thus pave the road towards novel treatment options.     

Predictive association of copper metabolism proteins with Alzheimer’s disease and Parkinson’s disease: a preliminary perspective

Neurodegenerative diseases, Alzheimer’s disease (AD) and Parkinson’s disease (PD), constitute a major worldwide health problem. Several hypothesis have been put forth to elucidate the basis of onset and pathogenesis of AD and PD; however, till date, none of these seems to clearly elucidate the complex pathoetiology of these disorders. Notably, copper dyshomeostasis has been shown to underlie the pathophysiology of several neurodegenerative diseases including AD and PD. Numerous studies have concluded beyond doubt that imbalance in copper homeostatic mechanisms in conjunction with aging causes an acceleration in the copper toxicity elicited oxidative stress, which is detrimental to the central nervous system. Amyloid precursor protein and α-synuclein protein involved in AD and PD are copper binding proteins, respectively. In this review, we have discussed the possible association of copper metabolism proteins with AD and PD along with briefly outlining the expanding proportion of “copper interactome” in human biology. Using network biology, we found that copper metabolism proteins, superoxide dismutase 1 and ceruloplasmin may represent direct and indirect link with AD and PD, respectively.     

Analyzing Large-Scale Samples Confirms the Association Between the ABCA7 rs3764650 Polymorphism and Alzheimer’s Disease Susceptibility

Large-scale genome-wide association studies (GWAS) have revealed that the ABCA7 rs3764650 polymorphism (or its proxies, namely rs115550680, rs3752246, and rs4147929) is associated with Alzheimer’s disease (AD) susceptibility in individuals of Caucasian ancestry. The following studies have investigated this finding in Chinese (N?=?633 and N?=?1,224), Japanese (N?=?1,735), Korean (N?=?844), African American (N?=?5,896), and Canadian (N?=?1,104) populations. However, these studies reported a weak or negligible association. We hypothesized that these negative results may have been caused by either relatively small sample sizes compared with those used for the previous GWAS in individuals of Caucasian ancestry or the genetic heterogeneity of the rs3764650 polymorphism (or its proxies) in different populations. Here, we reevaluated the association between rs3764650 and AD using large-scale samples from 18 previous studies (N?=?79,381—30,590 cases and 48,791 controls) by searching PubMed, AlzGene, and Google Scholar databases. Using allele, dominant, recessive, and additive models, we did not identify significant heterogeneity among the 18 studies. We observed a significant association between rs3764650 and AD using the allele (P?=?1.76E???26, odds ratio (OR)?=?1.21, 95 % confidence interval (CI) 1.17–1.26), dominant (P?=?4.00E???04, OR?=?1.17, 95 % CI 1.07–1.28), recessive (P?=?3.00E???03, OR?=?1.43, 95 % CI 1.13–1.81), and additive models (P?=?3.00E???03, OR?=?1.49, 95 % CI 1.16–1.91). Collectively, our analysis further supports previous findings that the ABCA7 rs3764650 polymorphism is associated with AD susceptibility. We believe that our findings will be very useful for future genetic studies on AD.     

PICALM rs3851179 Variant Confers Susceptibility to Alzheimer’s Disease in Chinese Population

The association between PICALM rs3851179 variant and Alzheimer’s disease (AD) has been well established by previous genome-wide association studies (GWAS) and candidate gene studies in European population. Recent studies investigated the association between PICALM rs3851179 and AD susceptibility in Chinese population. However, these studies reported consistent and inconsistent results. Here, we selected 9435 samples including 3704 AD cases and 5731 controls from previous studies and evaluated this association using a meta-analysis method for additive model. We did not observe significant genetic heterogeneity in Chinese population. Our results indicate significant association between PICALM rs3851179 and AD in Chinese population. The sensitivity analysis indicates that the association between rs3851179 and AD did not vary substantially. The regression analysis suggests no significant publication bias. In summary, this updated meta-analysis highlights the involvement of PICALM rs3851179 variant in Alzheimer’s disease susceptibility in Chinese population.     

Association of amyloid precursor protein-binding protein,family B,member 1 with nicotine dependence in African and European American smokers

Although epidemiological studies reveal that cigarette smoking is inversely associated with Alzheimer’s disease (AD) and Parkinson’s disease (PD), the underlying mechanism remains largely unknown. Considering the facts that amyloid precursor protein-binding protein, family B, member 1 (APBB1) is mapped to a suggestive linkage region on chromosome 11 for nicotine dependence (ND), and has been implicated in the pathogenesis of AD and PD, it represents a plausible candidate for genetic study of ND. Five single nucleotide polymorphisms (SNPs) within APBB1 were genotyped in a sample consisting of 2,037 participants of either African-American (AA) or European-American (EA) origin, and examined their associations with ND assessed by three commonly used measures: Smoking Quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerström Test for ND (FTND). Individual SNP-based association analysis showed that all five SNPs are associated with at least one ND measure in one of the three samples; however, only the association of SNP rs4758416 with SQ and HSI remained significant after correction for multiple testing in the pooled sample. Haplotype analysis demonstrated three major haplotypes significantly associated with ND after Bonferroni correction. Formed by rs4758416-rs10839562-rs1079199, haplotype C-C-T showed positive association with FTND in the AA and pooled samples, and conversely, haplotype G-C-T showed negative association with SQ and HSI in AA and EA samples. Another haplotype, C-T-G, formed by rs10839562-rs1079199-rs8164, was significantly associated with HSI in the EA sample. Based on these findings, we conclude that APBB1 represents an important candidate gene in the genetic study on ND and neurodegenerative diseases and warrants further investigation in future.     

Genetic polymorphism of interleukin 1β −511C/T and susceptibility to sporadic Alzheimer’s disease: a meta-analysis

A large number of epidemiological studies have been performed to investigate the association between Alzheimer’s disease (AD) risk and interleukin-1β ?511C/T genetic polymorphism, however, inconsistent results have been reported. The effect of the IL-1β ?511C/T polymorphism on AD susceptibility was evaluated by a meta-analysis. Series of databases were researched. 14 studies involving 2640 AD case and 3493 control subjects were identified. The pooled results showed there were no statistical associations of interleukin-1β ?511C/T genetic polymorphism with susceptibility to AD for five analysis models in all subjects. However, obvious heterogeneity among studies was detected. When stratifying for age at onset, ethnicity and geographic distribution of population to explore the original source of heterogeneity, the meta-analysis results based on geographic distribution of population showed the significant difference (CC vs CT, OR 1.26, 95 % CI: 1.03, 1.54, z = 2.25, P = 0.025; CC vs CT+TT, OR 1.24, 95 % CI: 1.03, 1.50, z = 2.24, P = 0.025) only in non-Europe. These findings indicate that the IL-1β ?511C/T polymorphism might be associated with AD risk, and individuals with IL-1β ?511C/C genotype might be at higher risk of AD in non-Europe. Further larger sample research would be warranted to confirm these conclusions.     

Nontraditional approaches to biomedical screening: Communication II

On the basis of theoretical studies and literature data, biochemical markers of multifactorial diseases (such as presenile dementia (PD) or Alzheimer’s disease (AD), multiple sclerosis (MS), and rheumatoid arthritis (RA), reflecting the pathogenetic features of these diseases have been systematized. Amyloid β is regarded as a common marker for PD (AD) and RA (along with the BB isozyme of creatine kinase, transaminase, α and -β secretases, acetylcholine, choline acetyltransferase, and acetylcholine esterase); myelin basic protein, tumor necrosis factor α, cephalin, and linoleic acid, as markers of MS; and circulating immune complexes, rheumatoid factor (RF IgG), granzyme A, perforin, acid phosphatase, and cathepsins, as markers of RA. Their contents in biological material obtained from patients were significantly higher or lower than in similar material from healthy subjects. Changes in the levels of some markers in patients were correlated with the severity of the corresponding diseases. Arguments are presented for the possibility of nontraditional biomedical screening of potential means of “molecular biochemical treatment” of these diseases by testing biologically active compounds for these markers.     

Genetic discoveries and advances in late-onset Alzheimer’s disease

Alzheimer’s disease (AD) is a heterogeneous disorder with multiple patterns of clinical manifestations. Recently, due to the advance of linkage studies, next-generation sequencing and genome-wide association studies, a large number of putative risk genes for AD have been identified using acquired genome mega data. The genetic association between three causal genes, including amyloid precursor protein, presenilin1, and presenilin2 in early-onset AD (EOAD), was discovered over the past few decades. These discoveries showed that there should be additional genetic risk factors for both EOAD and late-onset AD (LOAD) to help fully explain the leading molecular mechanisms in a single pathophysiological entity. This study reviews the clinical features and genetic etiology of LOAD and discusses a variety of AD-mediated genes that are involved in cholesterol and lipid metabolism, endocytosis, and immune response according to their mutations for more efficient selection of functional candidate genes for LOAD. New mechanisms and pathways have been identified as a result.     

Comprehensive research synopsis and systematic meta-analyses in Parkinson's disease genetics: The PDGene database

More than 800 published genetic association studies have implicated dozens of potential risk loci in Parkinson's disease (PD). To facilitate the interpretation of these findings, we have created a dedicated online resource, PDGene, that comprehensively collects and meta-analyzes all published studies in the field. A systematic literature screen of -27,000 articles yielded 828 eligible articles from which relevant data were extracted. In addition, individual-level data from three publicly available genome-wide association studies (GWAS) were obtained and subjected to genotype imputation and analysis. Overall, we performed meta-analyses on more than seven million polymorphisms originating either from GWAS datasets and/or from smaller scale PD association studies. Meta-analyses on 147 SNPs were supplemented by unpublished GWAS data from up to 16,452 PD cases and 48,810 controls. Eleven loci showed genome-wide significant (P < 5 × 10(-8)) association with disease risk: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SNCA, STK39, and SYT11/RAB25. In addition, we identified novel evidence for genome-wide significant association with a polymorphism in ITGA8 (rs7077361, OR 0.88, P = 1.3 × 10(-8)). All meta-analysis results are freely available on a dedicated online database (www.pdgene.org), which is cross-linked with a customized track on the UCSC Genome Browser. Our study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies.     

Null genotype of GSTT1 contributes to increased Parkinson’s disease risk in Caucasians: evidence from a meta-analysis

Conflicting results in previous case–control studies on the association between Glutathione S-transferase T1 (GSTT1) gene polymorphism and Parkinson’s disease (PD) risk have been reported, so we conducted this meta-analysis. We searched and extracted data from 3 Chinese and 3 English web-based electronic databases to evaluate the associations by odds ratio (OR) and its 95 % confidence interval (CI) under the recessive genetic comparison model (null genotype vs. present genotype). We also conducted subgroup analyses by ethnicity and adjusted status of OR, respectively. Meta-analyses and subgroup analyses of larger studies (sample size ≥300) were also reanalyzed. When 18 eligible studies (3,963 PD cases and 5,472 controls) were pooled to analyze the association, we found no statistically significant result (OR 1.24, 95 % CI 0.96–1.60). In the subgroup analyses by ethnicity, there was statistically significant association between the null genotype of GSTT1 and PD risk among Caucasians, while the associations were not found among Asians and Latinos. In the subgroup analyses by adjusted status of OR, there were no significant associations both in studies with crude OR and adjusted OR. Meta-analyses and subgroup analyses of larger studies (sample size ≥300) were also confirmed the associations mentioned above. Power analysis indicated only meta-analysis of Caucasians had enough evidence to claim the association. In conclusion, the meta-analysis suggests that the null genotype of GSTT1 contributes to PD risk in Caucasians, and no association in Asians is needed more studies to confirm.     

Interaction between genes and environment in neurodegenerative diseases

Alzheimer's disease (AD) and Parkinson's disease (PD) are highly prevalent disorders that account for a large part of the global burden of neurodegenerative diseases. Most AD and PD cases occur sporadically and it is generally agreed that they could arise through interactions among genetic and environmental factors. Candidate genes involved in the metabolism of xenobiotics, neurodegeneration and functioning of dopaminergic neurons were found to be associated with PD. Some of these genes interact with environmental factors that could modify PD risk. Thus, we found that the inverse association between smoking and the risk of PD depended on a polymorphism of the iNOS (inducible NO synthase) gene. We also found that the cytochrome P450 2D6 gene could have a modifying effect on the risk of PD among persons exposed to pesticides. Both interactions have biological plausibility supported by laboratory studies and could contribute to better understand the aetiology of PD. A single susceptibility gene has been identified in sporadic AD. The epsilon4 allele of epsilon polymorphism of the apolipoprotein E gene (APOE) is strongly associated with AD, the risk of AD being multiplied by 5 in persons carrying two epsilon4 alleles. The mechanism of the association between APOE and AD is poorly understood. A few interactions between the epsilon polymorphism and possible risk factors for AD have been described. However, these interactions had no biological plausibility and were likely due to chance.     

Neural regeneration therapies for Alzheimer's and Parkinson's disease-related disorders

Neurodegenerative diseases are devastating mental illnesses without a cure. Alzheimer's disease (AD) characterized by memory loss, multiple cognitive impairments, and changes in personality and behavior. Although tremendous progress has made in understanding the basic biology in disease processes in AD and PD, we still do not have early detectable biomarkers for these diseases. Just in the United States alone, federal and nonfederal funding agencies have spent billions of dollars on clinical trials aimed at finding drugs, but we still do not have a drug or an agent that can slow the AD or PD disease process. One primary reason for this disappointing result may be that the clinical trials enroll patients with AD or PD at advances stages. Although many drugs and agents are tested preclinical and are promising, in human clinical trials, they are mostly ineffective in slowing disease progression. One therapy that has been promising is ‘stem cell therapy’ based on cell culture and pre-clinical studies. In the few clinical studies that have investigated therapies in clinical trials with AD and PD patients at stage I. The therapies, such as stem cell transplantation – appear to delay the symptoms in AD and PD. The purpose of this article is to describe clinical trials using 1) stem cell transplantation methods in AD and PD mouse models and 2) regenerative medicine in AD and PD mouse models, and 3) the current status of investigating preclinical stem cell transplantation in patients with AD and PD.     

Association of heat-shock proteins in various neurodegenerative disorders: is it a master key to open the therapeutic door?

A number of acute and chronic neurodegenerative disorders are caused due to misfolding and aggregation of many intra- and extracellular proteins. Protein misfolding and aggregation processes in cells are strongly regulated by cellular molecular chaperones known as heat-shock proteins (Hsps) that include Hsp60, Hsp70, Hsp40, and Hsp90. Recent studies have shown the evidences that Hsps are colocalized in protein aggregates in Alzheimer’s disease (AD), Parkinson’s disease (PD), Polyglutamine disease (PGD), Prion disease, and other neurodegenerative disorders. This fact indicates that Hsps might have attempted to prevent aggregate formation in cells and thus to suppress disease conditions. Experimental findings have already established in many cases that selective overexpression of Hsps like Hsp70 and Hsp40 prevented the disease progression in various animal models and cellular models. However, recently, various Hsp modulators like geldanamycin, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin, and celastrol have shown to up-regulate the expression level of Hsp70 and Hsp40, which in turn triggers the solubilization of diseased protein aggregates. Hsps are, therefore, if appropriately selected, an attractive choice for therapeutic targeting in various kinds of neurodegeneration and hence are expected to have strong potential as therapeutic agents in suppressing or curing AD, PD, PGD, and other devastative neurodegenerative disorders. In the present review, we report the experimental findings that describe the implication of Hsps in the development of neurodegeneration and explore the possibility of how Hsps can be used directly or as a target by other agents to prevent various neurodegeneration through preventing aggregation process and thus reducing the toxicity of the oligomers based on the previous reports.     

Oligomers on the brain: the emerging role of soluble protein aggregates in neurodegeneration

Extracellular fibrous amyloid deposits or intracellular inclusion bodies containing abnormal protein fibrils characterize many different neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), dementia with Lewy bodies, multiple system atrophy, Huntington's disease, and the transmissible 'prion' dementias. There is strong evidence from genetic, transgenic mouse and biochemical studies to support the idea that the accumulation of protein aggregates in the brain plays a seminal role in the pathogenesis of these diseases. How monomeric proteins ultimately convert to highly polymeric deposits is unknown. However, studies employing, synthetic, cell-derived and purified recombinant proteins suggest that amyloid proteins first come together to form soluble low n-oligomers. Further association of these oligomers results in higher molecular weight assemblies including so-called 'protofibrils' and 'ADDLs' and these eventually exceed solubility limits until, finally, they are deposited as amyloid fibrils. With particular reference to AD and PD, we review recent evidence that soluble oligomers are the principal pathogenic species that drive neuronal dysfunction.     

Icariin: A Potential Neuroprotective Agent in Alzheimer’s Disease and Parkinson’s Disease

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative diseases worldwide. They are characterized by the loss of neurons and synapses in special parts of the central nervous system (CNS). There is no definitive treatment for AD and PD, but extensive studies are underway to identify the effective drugs which can slow the progression of these diseases by affecting the factors involved in their pathophysiology (i.e., aggregated proteins, neuroinflammation, and oxidative stress). Icariin, a natural compound isolated from Epimedii herba, is known because of its anti-inflammatory and anti-oxidant properties. In this regard, there are numerous studies indicating its potential as a natural compound against the progression of CNS disorders, such as neurodegenerative diseases. Therefore, this review aims to re-examine findings on the pharmacologic effects of icariin on factors involved in the pathophysiology of AD and PD.

     

Oxidative modifications and aggregation of Cu,Zn-superoxide dismutase associated with Alzheimer and Parkinson diseases

Although oxidative stress has been strongly implicated in the pathogenesis of Alzheimer disease (AD) and Parkinson disease (PD), the identities of specific protein targets of oxidative damage remain largely unknown. Here, we report that Cu,Zn-superoxide dismutase (SOD1), a key antioxidant enzyme whose mutations have been linked to autosomal dominant neurodegenerative disorder familial amyotrophic lateral sclerosis (ALS), is a major target of oxidative damage in AD and PD brains. By using a combination of two-dimensional gel electrophoresis, immunoblot analysis, and mass spectrometry, we have identified four human brain SOD1 isoforms with pI values of 6.3, 6.0, 5.7, and 5.0, respectively. Of these, the SOD1 pI 6.0 isoform is oxidatively modified by carbonylation, and the pI 5.0 isoform is selectively accumulated in AD and PD. Moreover, Cys-146, a cysteine residue of SOD1 that is mutated in familial ALS, is oxidized to cysteic acid in AD and PD brains. Quantitative Western blot analyses demonstrate that the total level of SOD1 isoforms is significantly increased in both AD and PD. Furthermore, immunohistochemical and double fluorescence labeling studies reveal that SOD1 forms proteinaceous aggregates that are associated with amyloid senile plaques and neurofibrillary tangles in AD brains. These findings implicate, for the first time, the involvement of oxidative damage to SOD1 in the pathogenesis of sporadic AD and PD. This work suggests that AD, PD, and ALS may share a common or overlapping pathogenic mechanism(s) that could potentially be targeted by similar therapeutic strategies.     

Function and dysfunction of leucine-rich repeat kinase 2 (LRRK2): Parkinson’s disease and beyond

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson’s disease (PD). As such, functions and dysfunctions of LRRK2 in PD have been the subject of extensive investigation. In addition to PD, increasing evidence is suggesting that LRRK2 is associated with a wide range of diseases. Genome-wide association studies have implicated LRRK2 in Crohn’s disease (CD) and leprosy, and the carriers with pathogenic mutations of LRRK2 show increased risk to develop particular types of cancer. LRRK2 mutations are rarely found in Alzheimer’s disease (AD), but LRRK2 might play a part in tauopathies. The association of LRRK2 with the pathogenesis of apparently unrelated diseases remains enigmatic, but it might be related to the yet unknown diverse functions of LRRK2. Here, we reviewed current knowledge on the link between LRRK2 and several diseases, including PD, AD, CD, leprosy, and cancer, and discussed the possibility of targeting LRRK2 in such diseases. [BMB Reports 2015; 48(5): 243-248]     

Progranulin polymorphism rs5848 is associated with increased risk of Alzheimer's disease

Progranulin is the precursor of granulins, and its down-regulation leads to neurodegeneration. Recent studies have indicated an association of progranulin polymorphism rs5848 with Alzheimer's disease (AD) risk, but the results remain controversial. To verify the association between rs5848 and AD risk, we retrieved the published literature from PubMed and other databases, and performed a meta-analysis by pooling all five studies containing 2502 AD cases and 2162 controls. The results showed that rs5848 is associated with increased risk of AD in homozygous (TT vs. CC: OR, 1.36; 95% CI, 1.11–1.66; P = 0.003) and recessive models (TT vs. CC + CT: OR, 1.31; 95% CI, 1.08–1.58; P = 0.006). This association was remained in Caucasian (2227 cases and 1902 controls). Our data indicate that TT allele of rs5848 is associated with increased risk of AD, suggesting that genetic variant of progranulin gene may play an important role in AD development.     

Mesenchymal stromal cells (MSCs) for neurodegenerative disease: A promising frontier

Neurodegenerative disorders are a variety of diseases including Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases (HD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) along with some other less common diseases generally described by the advanced deterioration of central or peripheral nervous system, structurally or functionally. In the last two decades, mesenchymal stromal cells (MSCs) due to their unique assets encompassing self-renewal, multipotency and accessibility in association with low ethical concern open new frontiers in the context of neurodegenerative diseases therapy. Interestingly, MSCs can be differentiated into endodermal and ectodermal lineages (e.g., neurons, oligodendrocyte, and astrocyte), and thus could be employed to advance cell-based therapeutic strategy. Additionally, as inflammation ordinarily ensues as a local response provoked by microglia in the neurodegenerative diseases, MSCs therapy because of their pronounced immunomodulatory properties is noticed as a rational approach for their treatment. Recently, varied types of studies have been mostly carried out in vitro and rodent models using MSCs upon their procurement from various sources and expansion. The promising results of the studies in rodent models have motivated researchers to design and perform several clinical trials, with a speedily rising number. In the current review, we aim to deliver a brief overview of MSCs sources, expansion strategies, and their immunosuppressive characteristics and discuss credible functional mechanisms exerted by MSCs to treat neurodegenerative disorders, covering AD, PD, ALS, MS, and HD.     

The Pathogenic Implication of Abnormal Interaction Between Apolipoprotein E Isoforms, Amyloid-beta Peptides, and Sulfatides in Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common cause of dementia in the aging population. Prior work has shown that the ε4 allele of apolipoprotein E (apoE4) is a major risk factor for “sporadic” AD, which accounts for >99% of AD cases without a defined underlying mechanism. Recently, we have demonstrated that sulfatides are substantially and specifically depleted at the very early stage of AD. To identify the mechanism(s) of sulfatide loss concurrent with AD onset, we have found that: (1) sulfatides are specifically associated with apoE-associated particles in cerebrospinal fluid (CSF); (2) apoE modulates cellular sulfatide levels; and (3) the modulation of sulfatide content is apoE isoform dependent. These findings not only lead to identification of the potential mechanisms underlying sulfatide depletion at the earliest stages of AD but also serve as mechanistic links to explain the genetic association of apoE4 with AD. Moreover, our recent studies further demonstrated that (1) apoE mediates sulfatide depletion in amyloid-β precursor protein transgenic mice; (2) sulfatides enhance amyloid β (Aβ) peptides binding to apoE-associated particles; (3) Aβ42 content notably correlates with sulfatide content in CSF; (4) sulfatides markedly enhance the uptake of Aβ peptides; and (5) abnormal sulfatide-facilitated Aβ uptake results in the accumulation of Aβ in lysosomes. Collectively, our studies clearly provide a link between apoE, Aβ, and sulfatides in AD and establish a foundation for the development of effective therapeutic interventions for AD.