Encoding Amyloid Precursor Protein Research Articles

Probable Novel APP Met671Leu Mutation in a Chinese Han Family with Early-Onset Alzheimer's Disease.

Familial Alzheimer's disease (AD) is a rare disease caused by autosomal-dominant mutations. APP (encoding amyloid precursor protein), PSEN1 (encoding presenilin 1), and PSEN2 (encoding presenilin 2) are the most common genes cause dominant inherited AD. This study aimed to demonstrate a Chinese early-onset AD pedigree presenting as progressive memory impairment, apraxia, visual-spatial disorders, psychobehavioral disorders, and personality changes with a novel APP gene mutation. The family contains four patients, three carries and three normal family members. The proband underwent brain magnetic resonance imaging (MRI), 18F-fludeoxyglucose positron emission tomography (18F-FDG-PET), cerebrospinal fluid amyloid detection, 18F-florbetapir (AV-45) Positron Emission Computed Tomography (PET) imaging, whole-exome sequencing and Sanger sequencing. Brain MRI images showed brain atrophy, especially in the entorhinal cortex, temporal hippocampus, and lateral ventricle dilation. The FDG-PET showed hypometabolism in the frontotemporal, parietal, and hippocampal regions. 18F-florbetapir (AV-45) PET imaging showed cerebral cortex Aβ protein deposition. The cerebrospinal fluid amyloid protein test showed Aβ42/Aβ40 ratio decreases, pathological phosphor-tau level increases. Whole-exome sequencing detected a new missense mutation of codon 671 (M671L), which was a heterozygous A to T point mutation at position 2011 (c.2011A > T) in exon 16 of the amyloid precursor protein, resulting in the replacement of methionine to Leucine. The co-separation analysis was validated in this family. The mutation was found in 3 patients, 3 clinical normal members in the family, but not in the other 3 unaffected family members, 100 unrelated normal subjects, or 100 sporadic patients with AD. This mutation was probably pathogenic and novel in a Chinese Han family with early-onset AD.

Taking a color photo: A homozygous 25-bp deletion in Bace2 may cause brown-and-white coat color in giant pandas

Brown-and-white giant pandas (hereafter brown pandas) are distinct coat color mutants found exclusively in the Qinling Mountains, Shaanxi, China. However, its genetic mechanism has remained unclear since their discovery in 1985. Here, we identified the genetic basis for this coat color variation using a combination of field ecological data, population genomic data, and a CRISPR-Cas9 knockout mouse model. We de novo assembled a long-read-based giant panda genome and resequenced the genomes of 35 giant pandas, including two brown pandas and two family trios associated with a brown panda. We identified a homozygous 25-bp deletion in the first exon of Bace2, a gene encoding amyloid precursor protein cleaving enzyme, as the most likely genetic basis for brown-and-white coat color. This deletion was further validated using PCR and Sanger sequencing of another 192 black giant pandas and CRISPR-Cas9 edited knockout mice. Our investigation revealed that this mutation reduced the number and size of melanosomes of the hairs in knockout mice and possibly in the brown panda, further leading to the hypopigmentation. These findings provide unique insights into the genetic basis of coat color variation in wild animals.

Disrupted Maturation of Prefrontal Layer 5 Neuronal Circuits in an Alzheimer's Mouse Model of Amyloid Deposition.

Mutations in genes encoding amyloid precursor protein (APP) and presenilins (PSs) cause familial forms of Alzheimer's disease (AD), a neurodegenerative disorder strongly associated with aging. It is currently unknown whether and how AD risks affect early brain development, and to what extent subtle synaptic pathology may occur prior to overt hallmark AD pathology. Transgenic mutant APP/PS1 over-expression mouse lines are key tools for studying the molecular mechanisms of AD pathogenesis. Among these lines, the 5XFAD mice rapidly develop key features of AD pathology and have proven utility in studying amyloid plaque formation and amyloid β (Aβ)-induced neurodegeneration. We reasoned that transgenic mutant APP/PS1 over-expression in 5XFAD mice may lead to neurodevelopmental defects in early cortical neurons, and performed detailed synaptic physiological characterization of layer 5 (L5) neurons from the prefrontal cortex (PFC) of 5XFAD and wild-type littermate controls. L5 PFC neurons from 5XFAD mice show early APP/Aβ immunolabeling. Whole-cell patch-clamp recording at an early post-weaning age (P22-30) revealed functional impairments; although 5XFAD PFC-L5 neurons exhibited similar membrane properties, they were intrinsically less excitable. In addition, these neurons received smaller amplitude and frequency of miniature excitatory synaptic inputs. These functional disturbances were further corroborated by decreased dendritic spine density and spine head volumes that indicated impaired synapse maturation. Slice biotinylation followed by Western blot analysis of PFC-L5 tissue revealed that 5XFAD mice showed reduced synaptic AMPA receptor subunit GluA1 and decreased synaptic NMDA receptor subunit GluN2A. Consistent with this, patch-clamp recording of the evoked L23>L5 synaptic responses revealed a reduced AMPA/NMDA receptor current ratio, and an increased level of AMPAR-lacking silent synapses. These results suggest that transgenic mutant forms of APP/PS1 overexpression in 5XFAD mice leads to early developmental defects of cortical circuits, which could contribute to the age-dependent synaptic pathology and neurodegeneration later in life.

Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis.

Alzheimer's disease (AD) is a debilitating dementia characterized by progressive memory loss and aggregation of amyloid-β (Aβ) protein into amyloid plaques in patient brains. Mutations in presenilin (PS) lead to abnormal generation of Aβ, which is the major cause of familial AD (FAD), and apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) onset. However, whether dysfunction of PS is involved in the pathogenesis of SAD is largely unknown. We found that ApoE secretion was completely abolished in PS-deficient cells and markedly decreased by inhibition of γ-secretase activity. Blockade of γ-secretase activity by a γ-secretase inhibitor, DAPT, decreased ApoE secretion, suggesting an important role of γ-secretase activity in ApoE secretion. Reduced ApoE secretion is also observed in nicastrin-deficient cells with reduced γ-secretase activity. PS deficiency enhanced nuclear translocation of ApoE and binding of ApoE to importin α4, a nuclear transport receptor. Moreover, the expression of PS mutants in PS-deficient cells suppressed the restoration effects on ApoE secretion compared with the expression of wild-type PS. Plasma ApoE levels were lower in FAD patients carrying PS1 mutations compared with normal control subjects. Our findings suggest a novel role of PS contributing to the pathogenesis of SAD by regulating ApoE secretion.SIGNIFICANCE STATEMENT Familial AD (FAD) typically results from mutations in the genes encoding amyloid precursor protein, presenilin 1 (PS1), or PS2. Many PS mutants have been found to exert impaired γ-secretase activity and increased amyloid-β 42 (Aβ42)/Aβ40 ratio, which induce early amyloid deposition and FAD. On the other hand, apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) and contributes to AD pathogenesis because it has reduced Aβ clearance capability compared with ApoE3 and ApoE2. FAD and SAD have long been considered to be caused by these two independent mechanisms; however, for the first time, we demonstrated that PS is essential for ApoE secretion and PS mutants affected ApoE secretion in vitro and in human samples, suggesting a novel mechanism by which PS is also involved in SAD pathogenesis.

Aging with Down Syndrome-Where Are We Now and Where Are We Going?

Down syndrome (DS) is a form of accelerated aging, and people with DS are highly prone to aging-related conditions that include vascular and neurological disorders. Due to the overexpression of several genes on Chromosome 21, for example genes encoding amyloid precursor protein (APP), superoxide dismutase (SOD), and some of the interferon receptors, those with DS exhibit significant accumulation of amyloid, phospho-tau, oxidative stress, neuronal loss, and neuroinflammation in the brain as they age. In this review, we will summarize the major strides in this research field that have been made in the last few decades, as well as discuss where we are now, and which research areas are considered essential for the field in the future. We examine the scientific history of DS bridging these milestones in research to current efforts in the field. We extrapolate on comorbidities associated with this phenotype and highlight clinical networks in the USA and Europe pursuing clinical research, concluding with funding efforts and recent recommendations to the NIH regarding DS research.

Knock-in rats with homozygous PSEN1L435F Alzheimer mutation are viable and show selective γ-secretase activity loss causing low Aβ40/42 and high Aβ43

Familial forms of Alzheimer's disease (FAD) are caused by mutations in the gene encoding amyloid precursor protein, whose processing can result in formation of β-amyloid (Aβ). FAD can also result from mutations in the presenilin 1/2 (PSEN1/2) genes, whose protein products partially compose the γ-secretase complex that cleaves Aβ from amyloid precursor protein fragments. Psen1 KO mice and knock-in (KI) mice with homozygous FAD-associated L435F mutations (Psen1LF/LF) are embryonic and perinatally lethal, precluding a more rigorous examination of the effect of Alzheimer's disease–causing Psen1 mutations on neurodegeneration. Given that the rat is a more suitable model organism with regard to surgical interventions and behavioral testing, we generated a rat KI model of the Psen1LF mutation. In this study, we focused on young Psen1LF rats to determine potential early pathogenic changes caused by this mutation. We found that, unlike Psen1LF/LF mice, Psen1LF/LF rats survive into adulthood despite loss of γ-secretase activity. Consistent with loss of γ-secretase function, Psen1LF/LF rats exhibited low levels of Aβ38, Aβ40, and Aβ42 peptides. In contrast, levels of Aβ43, a longer and potentially more amyloidogenic Aβ form, were significantly increased in Psen1LF/LF and Psen1LF/w rats. The longer survival of these KI rats affords the opportunity to examine the effect of homozygous Psen1 Alzheimer's disease–associated mutations on neurodegeneration in older animals.

Leveraging preclinical models for the development of Alzheimer disease therapeutics.

A large number of mouse models have been engineered, characterized and used to advance biomedical research in Alzheimer disease (AD). Early models simply damaged the rodent brain through toxins or lesions. Later, the spread of genetic engineering technology enabled investigators to develop models of familial AD by overexpressing human genes such as those encoding amyloid precursor protein (APP) or presenilins (PSEN1 or PSEN2) carrying mutations linked to early-onset AD. Recently, more complex models have sought to explore the impact of multiple genetic risk factors in the context of different biological challenges. Although none of these models has proven to be a fully faithful reproduction of the human disease, models remain essential as tools to improve our understanding of AD biology, conduct thorough pharmacokinetic and pharmacodynamic analyses, discover translatable biomarkers and evaluate specific therapeutic approaches. To realize the full potential of animal models as new technologies and knowledge become available, it is critical to define an optimal strategy for their use. Here, we review progress and challenges in the use of AD mouse models, highlight emerging scientific innovations in model development, and introduce a conceptual framework for use of preclinical models for therapeutic development.

A novel role of HuR in -Epigallocatechin-3-gallate (EGCG) induces tumour cells apoptosis.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide.1 Inducing tumour cells apoptosis by chemotherapy is a common treatment modality for inoperable tumour.2 Some studies have shown that amyloid protein precursor (APP), which plays an important role in neuronal cells owing to their linkage with Alzheimer's disease,3 aberrantly altered in many types of cancers. However, the regulation of APP in tumour cells and its role in tumour cells remains unknown.‐Epigallocatechin‐3‐gallate (EGCG) has been shown to possess a wide range of pharmacological properties, including anti‐inflammatory and neuroprotective effects, which have been linked to the antioxidant/pro‐oxidant properties of its polyphenol constituents.4 Some studies have shown that EGCG inhibited hepatocellular carcinoma growth and induced apoptosis.5 We previously also found that EGCG induced neuroblastoma apoptosis via inhibition of amyloid precursor protein.6 However, little is known about the mechanism of EGCG on APP regulation in tumour. The RNA‐binding proteins (RBPs) interact with other proteins and RNAs to form different ribonucleoprotein (RNP) complexes, which participate in the post‐transcriptional regulation of RNAs and which orchestrate the fate of those RNAs.7 Human antigen R (HuR, also known as ELAVL1) is an important RNA‐binding protein. Some studies reported that HuR correlated with patient outcome in liver cancer and interacted with lncRNA‐{type:entrez-nucleotide,attrs:{text:AK058003,term_id:16554001,term_text:AK058003}}AK058003 to regulate proliferation and metastasis of hepatocellular carcinoma.7 Furthermore, in neurons, studies showed that HuD interacted with the 3’ UTRs of APP mRNA (encoding amyloid precursor protein) and BACE1 mRNA (encoding β‐site APP‐cleaving enzyme 1) and increased the half‐lives of these mRNAs.8 However, the role of HuR in APP expression and EGCG‐regulated APP expression in tumour is not clear. In this study, we first indicate that the role of EGCG in APP and ADAM10 regulation is mediated by HuR, result in tumour cells apoptosis via HuR‐Erk1/2‐APP/ADAM10 pathway, adding a new dimension to EGCG‐mediated regulation of APP and ADAM10 in cancer cell apoptosis.

Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer's disease

Causative mutations in the genes encoding amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2) account for a majority of cases of familial Alzheimer disease (FAD) inherited in an autosomal-dominant pattern. For the sake of characterizing mutations, index patients from 148 families with FAD were enrolled from mainland China. Sanger sequencing of the genes APP, PSEN1, and PSEN2 was performed to characterize the mutation spectrum of the Chinese population. Thirteen of 148 (8.8%) individuals had possible pathogenic APP, PSEN1, or PSEN2 variants, including 2 (15.4%) APP variants, 8 (61.5%) PSEN1 variants, and 3 (23.1%) PSEN2 variants. PSEN1 variants represented the largest proportion in Chinese FAD, and PSEN2 variants are responsible for late-onset FAD in China. Analysis of genetic-clinical correlations permitted the conclusion that FAD phenotypes were mainly influenced by specific genetic defects.

TREM2 - a key player in microglial biology and Alzheimer disease.

Alzheimer disease (AD) is a debilitating dementia believed to result from the deposition of extracellular amyloid-β (Aβ)-containing plaques followed by the formation of neurofibrillary tangles. Familial AD typically results from mutations in the genes encoding amyloid precursor protein (APP), presenilin 1 or presenilin 2. Variations in triggering receptor expressed on myeloid cells 2 (TREM2), one of several genes for which expression is restricted to microglia in the brain, have now been shown to increase the risk of developing late-onset AD. Microglia have been shown to respond to Aβ accumulation and neurodegenerative lesions, progressively acquiring a unique transcriptional and functional signature and evolving into disease-associated microglia (DAM). DAM attenuate the progression of neurodegeneration in certain mouse models, but inappropriate DAM activation accelerates neurodegenerative disease in other models. TREM2 is essential for maintaining microglial metabolic fitness during stress events, enabling microglial progression to a fully mature DAM profile and ultimately sustaining the microglial response to Aβ-plaque-induced pathology. Here, we review the current data detailing the role of TREM2 in microglial biology and AD.

Role of presynaptic calcium stores for neural network dysfunction in Alzheimer's disease.

Role of presynaptic calcium stores for neural network dysfunction in Alzheimer's disease.

Mutation burden profile in familial Alzheimer's disease cases from India

This study attempts to identify coding risk variants in genes previously implicated in Alzheimer's disease (AD) pathways, through whole-exome sequencing of subjects (N = 17) with AD, with a positive family history of dementia (familial AD). We attempted to evaluate the mutation burden in genes encoding amyloid precursor protein metabolism and previously linked to risk of dementias. Novel variants were identified in genes involved in amyloid precursor protein metabolism such as PSEN1 (chr 14:73653575, W161C, tgg > tgT), PLAT (chr 8:42039530,G272R), and SORL1 (chr11:121414373,G601D). The mutation burden assessment of dementia-related genes for all 17 cases revealed 45 variants, which were either shared across subjects, or were present in just the 1 patient. The study shows that the clinical characteristics, and genetic correlates, obtained in this sample are broadly comparable to the other studies that have investigated familial forms of AD. Our study identifies rare deleterious genetic variations, in the coding region of genes involved in amyloid signaling, and other dementia-associated pathways.

The beginnings of Alzheimer’s disease: A review on inflammatory, mitochondrial, genetic and epigenetic pathways

Alzheimer?s Disease (AD) is the most common cause of sporadic dementia, as it affects 60% of cognitive impaired patients; it commonly affects middle and late life, and it is considered an age-related disease. Early-onset familial AD is associated with mutations of the genes encoding amyloid precursor protein (APP), presenilin 1 (PS-1), or PS-2, resulting in the overproduction of amyloid beta-protein. Epidemiological and case-control studies have led to the identification of several risk factors for sporadic AD. The most concrete genetic risk factor for AD is the epsilon4 allele of apolipoprotein E gene (APOE). In addition, several genes such as CTNNA3, GAB2, PVRL2, TOMM40, and APOC1 are known to be the risk factors that contribute to AD pathogenesis. A direct role of interaction between genetic and environmental determinants has been proposed in an epigenetic dynamic for environmental factors operating during the preconceptual, fetal and infant phases of life. Also the the association between mtDNA inherited variants and multifactorial diseases and AD has been investigated by a number of studies that, however, didn?t reach a general consensus on the correlation between mtDNA haplogroups and AD.

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome.

Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP)--an Alzheimer disease risk factor--although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population.

Recent Advances from the Bench Toward the Bedside in Alzheimer's Disease

Recent Advances from the Bench Toward the Bedside in Alzheimer's Disease

HuD Regulates Coding and Noncoding RNA to Induce APP→Aβ Processing

The primarily neuronal RNA-binding protein HuD is implicated in learning and memory. Here, we report the identification of several HuD target transcripts linked to Alzheimer's disease (AD) pathogenesis. HuD interacted with the 3' UTRs of APP mRNA (encoding amyloid precursor protein) and BACE1 mRNA (encoding β-site APP-cleaving enzyme 1) and increased the half-lives of these mRNAs. HuD also associated with and stabilized the long noncoding (lnc)RNA BACE1AS, which partly complements BACE1 mRNA and enhances BACE1 expression. Consistent with HuD promoting production of APP and APP-cleaving enzyme, the levels of APP, BACE1, BACE1AS, and Aβ were higher in the brain of HuD-overexpressing mice. Importantly, cortex (superior temporal gyrus) from patients with AD displayed significantly higher levels of HuD and, accordingly, elevated APP, BACE1, BACE1AS, and Aβ than did cortical tissue from healthy age-matched individuals. We propose that HuD jointly promotes the production of APP and the cleavage of its amyloidogenic fragment, Aβ.

Genetic markers for diagnosis and pathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia in the elderly and represents an important and increasing clinical challenge in terms of diagnosis and treatment. Mutations in the genes encoding amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) are responsible for early-onset autosomal dominant AD. The ε4 allele of the apolipoprotein E (APOE) gene has been recognized as a major genetic risk factor for the more common, complex, late-onset AD. Fibrillar deposits by phosphorylated tau are also a key pathological feature of AD. The retromer complex also has been reported to late-onset AD. More recently, genome-wide association studies (GWASs) identified putative novel candidate genes associated with late-onset AD. Lastly, several studies showed that circulating microRNAs (miRNAs) in the cerebrospinal fluid (CSF) and blood serum of AD patients can be used as biomarkers in AD diagnosis. This review addresses the advances and challenges in determining genetic and diagnostic markers for complex AD pathogenesis.

Phenotypical difference of Amyloid Precursor Protein (APP) V717L mutation in Japanese family

BackgroundAlzheimer’s disease (AD) is the most common form of dementia. Mutations in genes such as those encoding amyloid precursor protein (APP), presenilin 1 and presenilin 2, are responsible for early-onset familial AD.Case presentationIn this study, we report a 275341 G > C (Val717Leu) mutation in the APP gene in a Japanese family with early onset AD by genetic screening. This mutation has previously been detected in European families. In the Japanese family we screened, the age at onset of AD was 47.1 ± 3.1 years old (n = 9; range, 42–52). The symptoms in the affected members included psychiatric vulnerability and focal signs such as pyramidal signs, epileptic seizures, and myoclonic discharges. An MR imaging study showed relatively mild atrophic changes in the bilateral hippocampus and cerebral cortices in all affected members compared with their clinical presentations.ConclusionWe conclude that the clinical features of Alzheimer’s disease can be different even when caused by the same mutation in the APP gene. Further clinical and genetic studies are required to clarify the relationship between phenotypes and genotypes.

Alzheimer Disease: Advances in Pathogenesis, Diagnosis, and Therapy

Alzheimer disease (AD)9, the most frequent cause of dementia in Western societies, affects approximately 5.5 million people in the US and more than 35 million people worldwide. Common symptoms of this disease include memory loss, confusion, irritability, and aggression. Normal bodily functions are progressively lost, with AD becoming fatal within 3 to 9 years after diagnosis. The major risk factor for AD is advanced age. After the age of 65 years, the incidence of AD doubles every 5 years. As the size of the elderly population increases, particularly the “baby boomers,” the prevalence will approach 30 to 60 million cases in the US alone by 2050. The pathogenesis of AD is not clear, but the major pathogenetic mechanisms that have been suggested include the accumulation of misfolded proteins in the aging brain, which causes oxidative and inflammatory damage, which in turn leads to energy failure and synaptic dysfunction. A very small proportion (<1%) of AD cases are familial with early onset, and such cases have been linked to mutations in genes encoding amyloid precursor protein (APP) and presenilins 1 and 2. There is also a strong genetic association between one variant of apolipoprotein E (apo E) and the risk for developing AD. Over the last 10 years, there has been increased interest in understanding the pathogenesis of this disease and in the development of new therapies. We interview 4 specialists and examine the latest advances in pathogenesis, diagnosis, and therapy for this debilitating disease. Can you summarize briefly some new insights into the pathogenesis of AD? JoAnne McLaurin: We have understood for years that the biggest risk factor for AD is aging. We are now starting to unravel the effects of aging on memory function and link this back to disease progression. New data have arisen that link …

Isolating Epilepsy Genes and Their Comorbidiites

The number of genes underlying monogenic epilepsies in human and animal models continues to grow as the clinical syndromes for a variety of heritable epilepsies yield to neurogenetic analysis. Interestingly, the diversity of co-morbid phenotypes linked to single epilepsy gene defects is also expanding. While many rare familial idiopathic epilepsy disorders are typically defined as pure seizure syndromes, many occur in the context of more complex clinical symptomatology. This is not surprising, since genes that alter cortical excitability are expressed in diverse brain networks, as well as in other tissues. In this brief review, two such genes are described. The gene encoding amyloid precursor protein along with related genes contributing to the accumulation of an aberrant peptide cleavage product, Aβ42, has now been placed in a molecular pathway mediating both the dementia of Alzheimer's Disease and seizures. A second gene, KCNQ1, encoding one of the voltage-sensitive ion channels contributing to membrane repolarisation in the heart, is co-expressed in both heart and brain where mutations contribute to cardiac arrhythmias, early mortality, and seizures. KCNQ1, a member of the cardiac LQTS gene family, is the first validated candidate gene for sudden unexplained death in epilepsy (SUDEP). The new strategy of searching for epilepsy genes linked to non-epileptic co-morbidity is providing illuminating examples of the role of neuronal network hyperexcitability in explaining the clinical spectrum of complex human neurological disorders that feature seizures.