Alzheimer's Disease Mutations Research Articles

Near infra-red light treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is a chronic neurodegenerative disease. The symptoms include memory and spatial learning difficulties, language disorders, and loss of motivation, which get worse over time, eventually ending in death. No effective treatments are available for AD, currently. Current treatments only attenuate symptoms temporarily and are associated with severe side effects. Near infra-red (NIR) light has been studied for a long time. We investigated the effect of NIR on AD using a transgenic mouse model, which was obtained by co-injecting two vectors carrying AD mutations in amyloid precursor protein (APP) and presenilin-1 (PSEN1) into C57BL/6J mice. The irradiation equipment consisted of an accommodating box and an LED array. The wavelength of NIR light emitted from LED was between 1040[Formula: see text]nm and 1090[Formula: see text]nm. The power density delivered at the level of the mice was approximately 15[Formula: see text]mW/cm2. Firstly, we treated the mice with NIR for 40 days. Then, the irradiation was suspended for 28 days. Finally, another 15 days treatment was brought to mice. We conducted Morris water maze and immunofluorescence analysis to evaluate the effects of treatment. Immunofluorescence analysis was based on measuring the quantity of plaques in mouse brain slices. Our results show that NIR light improves memory and spatial learning ability and reduces plaques moderately. NIR light represents a potential treatment for AD.

Analysis of neurodegenerative Mendelian genes in clinically diagnosed Alzheimer Disease.

Alzheimer disease (AD), Frontotemporal lobar degeneration (FTD), Amyotrophic lateral sclerosis (ALS) and Parkinson disease (PD) have a certain degree of clinical, pathological and molecular overlap. Previous studies indicate that causative mutations in AD and FTD/ALS genes can be found in clinical familial AD. We examined the presence of causative and low frequency coding variants in the AD, FTD, ALS and PD Mendelian genes, in over 450 families with clinical history of AD and over 11,710 sporadic cases and cognitive normal participants from North America. Known pathogenic mutations were found in 1.05% of the sporadic cases, in 0.69% of the cognitively normal participants and in 4.22% of the families. A trend towards enrichment, albeit non-significant, was observed for most AD, FTD and PD genes. Only PSEN1 and PINK1 showed consistent association with AD cases when we used ExAC as the control population. These results suggest that current study designs may contain heterogeneity and contamination of the control population, and that current statistical methods for the discovery of novel genes with real pathogenic variants in complex late onset diseases may be inadequate or underpowered to identify genes carrying pathogenic mutations.

Memantine inhibits β-amyloid aggregation and disassembles preformed β-amyloid aggregates

Memantine, an uncompetitive glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist, is widely used as a medication for the treatment of Alzheimer's disease (AD). We previously reported that chronic treatment of AD with memantine reduces the amount of insoluble β-amyloid (Aβ) and soluble Aβ oligomers in animal models of AD. The mechanisms by which memantine reduces Aβ levels in the brain were evaluated by determining the effect of memantine on Aβ aggregation using thioflavin T and transmission electron microscopy. Memantine inhibited the formation of Aβ(1–42) aggregates in a concentration-dependent manner, whereas amantadine, a structurally similar compound, did not affect Aβ aggregation at the same concentrations. Furthermore, memantine inhibited the formation of different types of Aβ aggregates, including Aβs carrying familial AD mutations, and disaggregated preformed Aβ(1–42) fibrils. These results suggest that the inhibition of Aβ aggregation and induction of Aβ disaggregation may be involved in the mechanisms by which memantine reduces Aβ deposition in the brain.

The integration site of the APP transgene in the J20 mouse model of Alzheimer’s disease

Background: Transgenic animal models are a widely used and powerful tool to investigate human disease and develop therapeutic interventions. Making a transgenic mouse involves random integration of exogenous DNA into the host genome that can have the effect of disrupting endogenous gene expression. The J20 mouse model of Alzheimer's disease (AD) is a transgenic overexpresser of human APP with familial AD mutations and has been extensively utilised in preclinical studies and our aim was to determine the genomic location of the J20 transgene insertion. Methods: We used a combination of breeding strategy and Targeted Locus Amplification with deep sequencing to identify the insertion site of the J20 transgene array. To assess RNA and protein expression of Zbtb20, we used qRT-PCR and Western Blotting. Results: We demonstrate that the J20 transgene construct has inserted within the genetic locus of endogenous mouse gene Zbtb20 on chromosome 16 in an array , disrupting expression of mRNA from this gene in adult hippocampal tissue. Preliminary data suggests that ZBTB20 protein levels remain unchanged in this tissue, however further study is necessary. We note that the endogenous mouse App gene also lies on chromosome 16, although 42 Mb from the Zbtb20 locus. Conclusions: These data will be useful for future studies utilising this popular model of AD, particularly those investigating gene interactions between the J20 APP transgene and other genes present on Mmu16 in the mouse.

Soluble Gamma-secretase Modulators Attenuate Alzheimer's β-amyloid Pathology and Induce Conformational Changes in Presenilin 1

A central pathogenic event of Alzheimer's disease (AD) is the accumulation of the Aβ42 peptide, which is generated from amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. We have developed a class of soluble 2-aminothiazole γ-secretase modulators (SGSMs) that preferentially decreases Aβ42 levels. However, the effects of SGSMs in AD animals and cells expressing familial AD mutations, as well as the mechanism of γ-secretase modulation remain largely unknown. Here, a representative of this SGSM scaffold, SGSM-36, was investigated using animals and cells expressing FAD mutations. SGSM-36 preferentially reduced Aβ42 levels without affecting either α- and β-secretase processing of APP nor Notch processing. Furthermore, an allosteric site was identified within the γ-secretase complex that allowed access of SGSM-36 using cell-based, fluorescence lifetime imaging microscopy analysis. Collectively, these studies provide mechanistic insights regarding SGSMs of this class and reinforce their therapeutic potential in AD.

Nanoplasmonic fiber tip probe detects significant reduction of intracellular Alzheimer\u2019s disease-related oligomers by curcumin

Considerable evidence shows critical roles of intracellular pathogenic events of Alzheimer’s disease (AD). In particular, intracellular amyloid-β accumulation and oligomerization are early AD pathologic processes, which may lead to changes in inflammatory molecules and other AD-related pathological components. Curcumin and its analogs have been identified as potential drug candidates for AD. However, the effects of curcumin on intracellular AD pathologic processes remain largely unknown. Here we utilized a recently developed nanoplasmonic fiber tip probe (nFTP) technology and investigated whether curcumin leads to intracellular AD pathologic changes. We showed that our nFTP technology could robustly detect intracellular AD-related protein changes caused by a well-known inflammation inducer and a familial AD mutation. Intriguingly, curcumin remarkably reduced the level of intracellular oligomers while modestly reduced the level of an inflammatory cytokine. Thus, our results provided evidence that curcumin’s mechanism of action in attenuating AD pathology is through a major role of decreasing oligomerization.

AWARENESS OF MUTATION STATUS IN PERSONS AT RISK FOR FAMILIAL ALZHEIMER’S DISEASE

Persons at-risk for inheriting autosomal dominant Alzheimer's disease (ADAD) mutations live under the specter of developing a devastating illness and as a result face very difficult life decisions. Though generally considered to begin insidiously in adulthood, there could be subtle manifestations of the presence of a mutation that only mutation carriers (MCs) would be aware of. We sought to assess the accuracy with which persons at-risk for inheriting ADAD mutations might assess their own genetic status. Seventy persons from families with ADAD at risk for Amyloid Precursor Protein (APP) (n=20) or Presenilin-1 (PSEN1) (n=50) mutations were given a questionnaire asking whether or not they thought they had inherited the causative mutation from their affected parent. Participants selected either “No”, “Yes”, or “Prefer not to answer.” Subjects who were already aware of their mutation status, were older than 5 years past the average age of dementia diagnosis in their family, or had a Clinical Dementia Rating global score greater than 0.5 were excluded. Participants were grouped in tertiles corresponding to their age from their family-specific age of expected dementia diagnosis; the youngest group (n=22) ranged from -35 to -19 years, the middle group (n=25) ranged from -18 to -11 years, and the oldest group (n=23) ranged from -10 to 5 years. Within each tertile, two-tailed Chi-square tests were used to assess the accuracy with which persons could guess their mutation status. Overall, 36% of participants chose “prefer not to answer”. For the youngest two tertiles, subjects’ predictions of their mutation status were not significantly different from chance. For the oldest age group, of the 7 non-carriers that indicated a choice, all 7 correctly speculated they had not inherited the mutation and of the 9 carriers that indicated a choice, 5 (55%) speculated they had. Though preliminary, our results suggest that persons at-risk for ADAD cannot accurately predict their mutation status until they approach the age at which the disease manifests. Though many persons prefer not to directly confront their mutation status, those who want to know should be encouraged to explore explicit genetic testing.

The Lesion Analysis of Cholinergic Neurons in 5XFAD Mouse Model in the Three-Dimensional Level of Whole Brain.

Cholinergic system is very important for many higher brain functions, including learning and memory. Cholinergic neurons, especially those in the basal forebrain, are specifically susceptible in some neurodegenerative diseases, such as in Alzheimer's disease (AD). Here, we studied the cholinergic system lesion effects of five familial AD mutations in 5XFAD mice, a transgenic mouse model of AD. Although the cholinergic system has been studied in this mouse model, the cholinergic deficits in AD mice have never been systematically mapped in a whole-brain three-dimensional (3D) reconstruction. Using the 3D reconstruction technology combined with immunohistochemistry (3D-IHC) and design-based stereology, we comprehensively compared the differences of the cholinergic neurons and fibers between the 5XFAD mice and C57BL/6 control mice at different age. Here, we found that the lesion of cholinergic fibers occurred earlier than the cholinergic neuron loss in 5XFAD mice. The cholinergic fiber lesions in the AD mice started sequentially in amygdala, cortex, hippocampus, and then basal forebrain. However, the basal forebrain was the first brain region observed with cholinergic neuron loss at the age of 9months in 5XFAD mice, whereas such phenomenon first occurred at the age of 15months in C57BL/6 control mice. Moreover, using 3D reconstruction to compare the lesion of cholinergic system of aged 5XFAD and C57BL/6 control mice, it is intuitive to notice the pathologic regions and severity of lesion. Therefore, the 3D-IHC provides detailed overview of the cholinergic neurons in the whole mouse brain, which will contribute to the study of the developing and pathologic mouse brain.

Entorhinal Cortical Deep Brain Stimulation Rescues Memory Deficits in Both Young and Old Mice Genetically Engineered to Model Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Deep brain stimulation (DBS) has been used to treat a variety of brain disorders and shows promise in alleviating cognitive symptoms in some AD patients (Laxton et al, 2010). We previously showed that DBS of the entorhinal cortex (EC) enhances spatial memory formation in normal (wild-type) mice (Stone et al, 2011). Here we tested the effects of EC-DBS on the progressive cognitive deficits in a genetically-based mouse model of AD. TgCRND8 (Tg) transgenic mice express human amyloid precursor protein harboring the Swedish and Indiana familial AD mutations. These mice exhibit age-related increases in Aβ production, plaque deposition, as well as contextual fear and spatial memory impairments. Here, we found EC stimulation in young mice (6 weeks old) rescued the early contextual fear and spatial memory deficits and decreased subsequent plaque load in Tg mice. Moreover, stimulation in older mice (6 months old) was also sufficient to rescue the memory deficits in Tg mice. The memory enhancement induced by DBS emerged gradually (over the course of weeks) and was both persistent and specific to hippocampal-based memories. These results provide further support for the development of novel therapeutics aimed to resolve the cognitive decline and memory impairment in AD using DBS of hippocampal afferents.

Habitual exercise levels are associated with cerebral amyloid load in presymptomatic autosomal dominant Alzheimer's disease

IntroductionThe objective of this study was to evaluate the relationship between self-reported exercise levels and Alzheimer's disease (AD) biomarkers, in a cohort of autosomal dominant AD mutation carriers. MethodsIn 139 presymptomatic mutation carriers from the Dominantly Inherited Alzheimer Network, the relationship between self-reported exercise levels and brain amyloid load, cerebrospinal fluid (CSF) Aβ42, and CSF tau levels was evaluated using linear regression. ResultsNo differences in brain amyloid load, CSF Aβ42, or CSF tau were observed between low and high exercise groups. Nevertheless, when examining only those already accumulating AD pathology (i.e., amyloid positive), low exercisers had higher mean levels of brain amyloid than high exercisers. Furthermore, the interaction between exercise and estimated years from expected symptom onset was a significant predictor of brain amyloid levels. DiscussionOur findings indicate a relationship exists between self-reported exercise levels and brain amyloid in autosomal dominant AD mutation carriers.

APOE ε4 specific imbalance of arachidonic acid and docosahexaenoic acid in serum phospholipids identifies individuals with preclinical Mild Cognitive Impairment/Alzheimer's Disease.

This study was designed to explore the influence of apolipoprotein E (APOE) on blood phospholipids (PL) in predicting preclinical Alzheimer's disease (AD). Lipidomic analyses were also performed on blood from an AD mouse model expressing human APOE isoforms (EFAD) and five AD mutations and from 195 cognitively normal participants, 23 of who converted to mild cognitive impairment (MCI)/AD within 3 years. APOE ε4-carriers converting to MCI/AD had high arachidonic acid (AA)/docosahexaenoic acid (DHA) ratios in PL compared to cognitively normal ε4 and non-ε4 carriers. Arachidonic acid and DHA containing PL species, ε4-status and Aβ42/Aβ40 ratios provided 91% accuracy in detecting MCI/AD. Fish oil/omega-3 fatty acid consumption was associated with lower AA/DHA ratios even among ε4 carriers. High plasma AA/DHA ratios were observed in E4FAD compared to EFAD mice with other isoforms. In particular, alterations in plasma AA and DHA containing PL species were also observed in the brains of E4FAD mice compared to E3FAD mice. Despite the small sample size and a short follow-up, these results suggest that blood PL could potentially serve as biomarkers of preclinical MCI/AD.

Plaque formation and the intraneuronal accumulation of β-amyloid in Alzheimer's disease.

Amyloid plaques and neurofibrillary tangles (NFTs) in the brain are the neuropathological hallmarks of Alzheimer's disease (AD). Amyloid plaques are composed of β-amyloid peptides (Aβ), while NFTs contain hyperphosphorylated tau proteins. Patients with familial AD who have mutations in the amyloid precursor protein (APP) gene have either increased production of Aβ or generate more aggregation-prone forms of Aβ. The findings of familial AD mutations in the APP gene suggest that Aβ plays a central role in the pathophysiology of AD. Aβ42, composed of 42 amino acid residues, aggregates readily and is considered to form amyloid plaque. However, the processes of plaque formation are still not well known. It is generally thought that Aβ is secreted into the extracellular space and aggregates to form amyloid plaques. Aβ as extracellular aggregates and amyloid plaques are thought to be toxic to the surrounding neurons. The intraneuronal accumulation of Aβ has more recently been demonstrated and is reported to be involved in synaptic dysfunction, cognitive impairment, and the formation of amyloid plaques in AD. We herein provide an overview of the process of the intraneuronal accumulation of Aβ and plaque formation, and discuss its implications for the pathology, early diagnosis, and therapy of AD.

TRPC5 Channels are Inhibited by Wt Presenilin1 but not the Alzheimer's Disease Mutant M146V

TRPC5 Channels are Inhibited by Wt Presenilin1 but not the Alzheimer's Disease Mutant M146V

Understanding the Role of Chain Flexibility in Amyloid Protein Aggregation through Rationally Designed Protein Sequences

The aggregation of amyloid proteins is associated with a myriad of medical conditions including Alzheimer's disease (AD), diabetes, and Parkinson's disease. While attributable to different amyloid proteins, these proteins all share a common feature: a periodic glycine motif (GxxxG). This glycine motif, associated with increased backbone flexibility, is extended in a number of familial mutations that significantly increase severity of AD. A better understanding of the role that chain flexibility plays in protein aggregation will allow for new and innovative protein engineering strategies for nanotech development as well as give insight into therapeutic strategies.In this study, the glycine motif is targeted via either extension, by introduction of additional periodic glycine, or contraction, by replacement of glycine with a bulky or constrained amino acid. Modifications that extend periodic glycine include those that align with familial AD mutations. To examine how these alterations to the glycine repeat motif impact aggregation kinetics, aggregation was monitored via thioflavin-T fluorescence and fit using a novel kinetic equation that accounts for unique features observed at late stages of aggregation. Aggregation products were visualized using transmission electron microscopy to examine morphological features. In addition, aggregates were fractionated by size exclusion chromatography for size analysis via light scattering and morphology analysis via surface hydrophobicity. Results indicate that increased chain flexibility correlates with faster nucleation as well as a larger quantity of small, intermediate aggregates that exhibit reduced fibril morphology with unchanged surface hydrophobicity. Taken together with observations that smaller aggregates are more physiologically active, these results support the hypothesis that increases in protein chain flexibility, including that associated with familial mutations, may contribute to disease progression.Future work will extend studies to other amyloid proteins, such as amylin and chaplin H.

Genetic Rescue of Mitochondrial Calcium Efflux in Alzheimer's Disease Preserves Mitochondrial Function and Protects against Neuronal Cell Death

Background. Alzheimer's disease (AD) is characterized by neurodegeneration, specifically the progressive loss of neuronal populations in the frontal cortex and hippocampus. Numerous studies have shown that neuronal cell death and metabolic dysregulation are fundamental cellular mechanisms driving the progression of AD and other dementia-related diseases. Previous studies have suggested numerous mechanisms whereby intracellular Ca2+ load is increased in AD and thereby likely significantly impacts mCa2+ signaling. Methods. To discern if mCa2+ signaling is causative in the progression of AD, human AD brain samples, an AD mutant mouse model (3xTg) and an AD-mutant cell line (N2a/APPswe) were examined for mitochondrial alterations in: Ca2+ handling, ROS generation, membrane potential (ΔΨ), permeability transition pore activation, OxPhos, APP metabolism and cell death. Results. 3xTg-AD mice and human AD brain samples displayed significant alterations in the expression of key mCa2+ exchange genes, most notably a reduction in the expression of the mitochondrial Na+/Ca2+ exchanger (mNCX, SLC8B1), the major efflux pathway in excitable cells. We discovered that mCa2+ efflux and mCa2+ retention capacity was severely impaired in N2a/APPswe cells. Rescue of mCa2+ extrusion, via adenoviral expression of mNCX, enhanced the clearance of pathogenic mCa2+, recovered (ΔΨ), enhanced OxPhos, reduced extracellular Aβ1-40 levels and protected from ionomycin-, glutamate- and ROS-induced cell death. Conclusions. Our data suggest that impaired mCa2+ exchange is a central contributor to neuronal cell death in AD and that mNCX represents a new therapeutic target to inhibit or reverse AD progression.

Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network.

Progranulin (PGRN) is implicated in Alzheimer's disease (AD) as well as frontotemporal lobar degeneration. Genetic studies demonstrate an association of the common GRN rs5848 variant that results in reduced PGRN levels with increased risk for AD. However, the mechanisms by which PGRN reduction from the GRN AD risk variant or mutation exacerbates AD pathophysiology remain ill defined. Here, we show that the GRN AD risk variant has no significant effects on florbetapir positron emission tomographic amyloid imaging and cerebrospinal fluid (CSF) Aβ levels, whereas it is associated with increased CSF tau levels in human subjects of the Alzheimer's disease neuroimaging initiative studies. Consistent with the human data, subsequent analyses using the APPswe/PS1ΔE9 (APP/PS1) mouse model of cerebral amyloidosis show that PGRN deficiency has no exacerbating effects on Aβ pathology. In contrast and unexpectedly, PGRN deficiency significantly reduces diffuse Aβ plaque growth in these APP/PS1 mice. This protective effect is due, at least in part, to enhanced microglial Aβ phagocytosis caused by PGRN deficiency-induced expression of TYROBP network genes (TNG) including an AD risk factor Trem2. PGRN-deficient APP/PS1 mice also exhibit less severe axonal dystrophy and partially improved behavior phenotypes. While PGRN deficiency reduces these amyloidosis-related phenotypes, other neuronal injury mechanisms are increased by loss of PGRN, revealing a multidimensional interaction of GRN with AD. For example, C1q complement deposition at synapses is enhanced in APP/PS1 mice lacking PGRN. Moreover, PGRN deficiency increases tau AT8 and AT180 pathologies in human P301L tau-expressing mice. These human and rodent data suggest that global PGRN reduction induces microglial TNG expression and increases AD risk by exacerbating neuronal injury and tau pathology, rather than by accelerating Aβ pathology.

The Effects of Gene Mutations onDefaultMode Network inFamilialAlzheimer's Disease.

Familial Alzheimer's disease (FAD) mutations have very high penetrance but age at onset and rate of disease progression differ. Neuroimaging and cerebrospinal fluid (CSF) examinations in mutation carriers (MCs) may provide an opportunity to identify early biomarkers that can be used to track disease progression from presymptomatic to the dementia stages of disease. The default mode network (DMN) is a resting state neuronal network composed of regions known to associate with amyloid deposition in AD. We hypothesized that functional connectivity in the DMN might change at pre-clinical stages in FAD MCs and correlate with changes in CSF biomarkers as a consequence of AD brain pathology. To test the hypothesis, we compared the functional connectivity in DMN between pre-MCs/MCs and non-carriers (NCs). No significant differences between pre-MCs and NCs were observed. When comparing all MCs with NCs, significant decreased functional connectivity in the right inferior parietal lobule, right precuneus, and left posterior cingulate cortex were found. We also found statistically significant correlations between CSF amyloid-β 42 and tau protein levels and average Z-score, a resting-state functional MRI measurement reflecting the degree of the correlation between a given voxel's time courses and the time courses corresponding to DMN, from the region with statistical difference. The observed disruption of DMN and pathological levels of AD CSF-biomarkers in FAD MCs are similar to the changes described in sporadic AD, which give further support that amyloid and tau pathology impairs neuronal and synaptic function.

Localization and Processing oftheAmyloid-β Protein Precursor inMitochondria-Associated Membranes.

Alteration of mitochondria-associated membranes (MAMs) has been proposed to contribute to the pathogenesis of Alzheimer’s disease (AD). We studied herein the subcellular distribution, the processing, and the protein interactome of the amyloid-β protein precursor (AβPP) and its proteolytic products in MAMs. We reveal that AβPP and its catabolites are present in MAMs in cellular models overexpressing wild type AβPP or AβPP harboring the double Swedish or London familial AD mutations, and in brains of transgenic mice model of AD. Furthermore, we evidenced that both β- and γ-secretases are present and harbor AβPP processing activities in MAMs. Interestingly, cells overexpressing APPswe show increased ER-mitochondria contact sites. We also document increased neutral lipid accumulation linked to Aβ production and reversed by inhibiting β- or γ-secretases. Using a proteomic approach, we show that AβPP and its catabolites interact with key proteins of MAMs controlling mitochondria and ER functions. These data highlight the role of AβPP processing and proteomic interactome in MAMs deregulation taking place in AD.

A genetic screen of the mutations in the Korean patients with early-onset Alzheimer's disease.

Early-onset Alzheimer’s disease (EOAD) has distinct clinical characteristics in comparison to late-onset Alzheimer’s disease (LOAD). The genetic contribution is suggested to be more potent in EOAD. However, the frequency of causative mutations in EOAD could be variable depending on studies. Moreover, no mutation screening study has been performed yet employing large population in Korea. Previously, we reported that the rate of family history of dementia in EOAD patients was 18.7% in a nationwide hospital-based cohort study, the Clinical Research Center for Dementia of South Korea (CREDOS) study. This rate is much lower than in other countries and is even comparable to the frequency of LOAD patients in our country. To understand the genetic characteristics of EOAD in Korea, we screened the common Alzheimer’s disease (AD) mutations in the consecutive EOAD subjects from the CREDOS study from April 2012 to February 2014. We checked the sequence of APP (exons 16–17), PSEN1 (exons 3–12), and PSEN2 (exons 3–12) genes. We identified different causative or probable pathogenic AD mutations, PSEN1 T116I, PSEN1 L226F, and PSEN2 V214L, employing 24 EOAD subjects with a family history and 80 without a family history of dementia. PSEN1 T116I case demonstrated autosomal dominant trait of inheritance, with at least 11 affected individuals over 2 generations. However, there was no family history of dementia within first-degree relation in PSEN1 L226F and PSEN2 V214L cases. Approximately, 55.7% of the EOAD subjects had APOE ε4 allele, while none of the mutation-carrying subjects had the allele. The frequency of genetic mutation in this study is lower compared to the studies from other countries. The study design that was based on nationwide cohort, which minimizes selection bias, is thought to be one of the contributors to the lower frequency of genetic mutation. However, the possibility of the greater likeliness of earlier onset of sporadic AD in Korea cannot be excluded. We suggest early AD onset and not carrying APOE ε4 allele are more reliable factors for predicting an induced genetic mutation than the presence of the family history in Korean EOAD population.

3D culture models of Alzheimer's disease: a road map to a "cure-in-a-dish".

Alzheimer’s disease (AD) transgenic mice have been used as a standard AD model for basic mechanistic studies and drug discovery. These mouse models showed symbolic AD pathologies including β-amyloid (Aβ) plaques, gliosis and memory deficits but failed to fully recapitulate AD pathogenic cascades including robust phospho tau (p-tau) accumulation, clear neurofibrillary tangles (NFTs) and neurodegeneration, solely driven by familial AD (FAD) mutation(s). Recent advances in human stem cell and three-dimensional (3D) culture technologies made it possible to generate novel 3D neural cell culture models that recapitulate AD pathologies including robust Aβ deposition and Aβ-driven NFT-like tau pathology. These new 3D human cell culture models of AD hold a promise for a novel platform that can be used for mechanism studies in human brain-like environment and high-throughput drug screening (HTS). In this review, we will summarize the current progress in recapitulating AD pathogenic cascades in human neural cell culture models using AD patient-derived induced pluripotent stem cells (iPSCs) or genetically modified human stem cell lines. We will also explain how new 3D culture technologies were applied to accelerate Aβ and p-tau pathologies in human neural cell cultures, as compared the standard two-dimensional (2D) culture conditions. Finally, we will discuss a potential impact of the human 3D human neural cell culture models on the AD drug-development process. These revolutionary 3D culture models of AD will contribute to accelerate the discovery of novel AD drugs.