Processing Of Beta-amyloid Precursor Protein Research Articles

Investigating the Synergistic Potential of Low-Dose HDAC3 Inhibition and Radiotherapy in Alzheimer’s Disease Models

We have previously shown that histone deacetylase (HDAC) inhibition and cranial radiotherapy (RT) independently improve molecular and behavioral Alzheimer’s disease (AD)-like phenotypes. In the present study, we investigate the synergistic potential of using both RT and HDACi as a low-dose combination therapy (LDCT) to maximize disease modification (reduce neuroinflammation and amyloidogenic APP processing, increase neurotrophic gene expression) while minimizing the potential for treatment-associated side effects.LDCT consisted of daily administration of the HDAC3 inhibitor RGFP966 and/or bi-weekly cranial x-irradiation. Amyloid-beta precursor protein (APP) processing and innate immune response to LDCT were assessed in vitro and in vivo using human and murine cell models and 3xTg-AD mice. After 2 months of LDCT in mice, behavioral analyses as well as expression and modification of key AD-related targets (Aβ, tau, Csf1r, Bdnf, etc.) were assessed in the hippocampus (HIP) and prefrontal cortex (PFC).LDCT induced a tolerant, anti-inflammatory innate immune response in microglia and increased non-amyloidogenic APP processing in vitro. Both RT and LDCT improved the rate of learning and spatial memory in the Barnes maze test. LDCT induced a unique anti-AD HIP gene expression profile that included upregulation of neurotrophic genes and downregulation of inflammation-related genes. RT lowered HIP Aβ42/40 ratio and Bace1 protein, while LDCT lowered PFC p-tau181 and HIP Bace1 levels.Our study supports the rationale for combining complementary therapeutic approaches at low doses to target multifactorial AD pathology synergistically. Namely, LDCT with RGFP966 and cranial RT shows disease-modifying potential against a wide range of AD-related hallmarks.

A CHCHD6–APP axis connects amyloid and mitochondrial pathology in Alzheimer’s disease

The mechanistic relationship between amyloid-beta precursor protein (APP) processing and mitochondrial dysfunction in Alzheimer’s disease (AD) has long eluded the field. Here, we report that coiled-coil-helix-coiled-coil-helix domain containing 6 (CHCHD6), a core protein of the mammalian mitochondrial contact site and cristae organizing system, mechanistically connects these AD features through a circular feedback loop that lowers CHCHD6 and raises APP processing. In cellular and animal AD models and human AD brains, the APP intracellular domain fragment inhibits CHCHD6 transcription by binding its promoter. CHCHD6 and APP bind and stabilize one another. Reduced CHCHD6 enhances APP accumulation on mitochondria-associated ER membranes and accelerates APP processing, and induces mitochondrial dysfunction and neuronal cholesterol accumulation, promoting amyloid pathology. Compensation for CHCHD6 loss in an AD mouse model reduces AD-associated neuropathology and cognitive impairment. Thus, CHCHD6 connects APP processing and mitochondrial dysfunction in AD. This provides a potential new therapeutic target for patients.

Golgi stress induces upregulation of the ER-Golgi SNARE Syntaxin-5, altered βAPP processing, and Caspase-3-dependent apoptosis in NG108-15 cells

The involvement of secretory pathways and Golgi dysfunction in neuronal cells during Alzheimer's disease progression is poorly understood. Our previous overexpression and knockdown studies revealed that the intracellular protein level of Syntaxin-5, an endoplasmic reticulum-Golgi soluble N-ethylmaleimide-sensitive factor-attachment protein receptor (SNARE), modulates beta-amyloid precursor protein processing in neuronal cells. We recently showed that changes in endogenous Syntaxin-5 protein expression occur under stress induction. Syntaxin-5 was upregulated by endoplasmic reticulum stress but was degraded by Caspase-3 during apoptosis in neuronal cells. In addition, we showed that sustained endoplasmic reticulum stress promotes Caspase-3-dependent apoptosis during the later phase of the endoplasmic reticulum stress response in NG108-15 cells. In this study, to elucidate the consequences of secretory pathway dysfunction in beta-amyloid precursor protein processing that lead to neuronal cell death, we examined the effect of various stresses on endoplasmic reticulum-Golgi SNARE expression and beta-amyloid precursor protein processing. By using compounds to disrupt Golgi function, we show that Golgi stress promotes upregulation of the endoplasmic reticulum-Golgi SNARE Syntaxin-5, and prolonged stress causes Caspase-3-dependent apoptosis. Golgi stress induced intracellular beta-amyloid precursor protein accumulation and a concomitant decrease in total amyloid-beta production. We also examined the protective effect of the chemical chaperone 4-phenylbutylate on changes in amyloid-beta production and the activation of Caspase-3 induced by endoplasmic reticulum and Golgi stress. The compound alleviated the increase in the amyloid-beta 1–42/amyloid-beta 1–40 ratio induced by endoplasmic reticulum and Golgi stress. Furthermore, 4-phenylbutylate could rescue Caspase-3-dependent apoptosis induced by prolonged organelle stress. These results suggest that organelle stress originating from the endoplasmic reticulum and Golgi has a substantial impact on the amyloidogenic processing of beta-amyloid precursor protein and Caspase-3-dependent apoptosis, leading to neuronal cell death.

Melatonin Attenuates High Glucose-Induced Changes in Beta Amyloid Precursor Protein Processing in Human Neuroblastoma Cells.

Diabetes mellitus (DM), one of metabolic diseases, has been suggested as a risk factor for Alzheimer's disease (AD). However, how the metabolic pathway activates amyloid precursor protein (APP) processing enzymes then contributes to the increase of amyloid-beta (Aβ) production, is not clearly understood. In the present study, we aimed to examine the protective effect of melatonin against hyperglycemia-induced alterations in the amyloidogenic pathway. High concentration of glucose was used to induce hyperglycemia in human neuroblastoma SH-SY5Y cells. We found that 30mM glucose affected the expression of insulin receptors and glucose transporters, which indicated the disruption of glucose sensing. High glucose induced the activation of the phosphorylated protein kinase B (pAkt)/GSK-3β signaling pathway and a significant increase in the expression of β-site beta APP cleaving enzyme (BACE1), presenilin1 (PS1) and Aβ42. Pretreatment with melatonin significantly reversed these parameters. We also showed that these effects are similar to those effects in the presence of the GSK-3β blocker, N-(4-methoxybenyl)-N'-(5-nitro-1,3-thiazol-2-yl) urea (ARA) in glucose-treated hyperglycemic cells. These suggested that melatonin exerted an inhibitory effect on the activation of APP-cleaving enzymes via the GSK-3β signaling pathway. Pretreatment with luzindole, a melatonin receptor MT1 antagonist, significantly prevented the effect of melatonin on the glucose-induced increase level of APP processing enzymes. This suggested that melatonin attenuated the toxic effect on hyperglycemia involving the amyloidogenic pathway partially mediated via melatonin receptor. Taken together the present results suggested that melatonin has a beneficial role in preventing Aβ generation in a cellular model of hyperglycemia-induced DM.

Role of Cdk5 in Amyloid-beta Pathology of Alzheimer's Disease.

Alzheimer's Disease (AD) is a progressive neurodegenerative disease with irreversible cognitive impairment. So far, successful treatment and prevention for this disease are deficient in spite of delaying the progression of cognitive impairment and dementia. Cyclin dependent kinase 5 (Cdk5), a unique member of the cyclin-dependent kinase family, is involved in AD pathogenesis and may be a pathophysiological mediator that links the major pathological features of AD. Cdk5 dysregulation interferes with the proteolytic processing of Amyloid-beta Protein Precursor (APP) and modulates amyloidbeta (Aβ) by affecting three enzymes called α-, β- and γ-secretase, which are critical for the hydrolysis of APP. Given that the accumulation and deposition of Aβ derived from APP are a common hinge point in the numerous pathogenic hypotheses of AD, figuring out that influence of specific mechanisms of Cdk5 on Aβ pathology will deepen our understanding of AD.

Inhibition of p-mTOR represses transcription of PS1 and Notch 1-signaling.

Presenilin-1 (PS1) protein is the catalytic subunit of the gamma-secretase, and participates in the processing of beta-amyloid precursor protein (APP) to produce Abeta peptide and Notch 1 receptor to release Notch intracellular domain (NICD) in the cytoplasm. NICD migrates to the nucleus and causes Notch signaling by increasing the expression of the Hes1 gene. The mammalian target of rapamycin (mTOR) controls cellular homeostasis, and its activity is inhibited by rapamycin. The buildup of Abeta increases the mTOR signaling, whereas decreasing mTOR signaling reduces Abeta levels suggesting an interrelationship between mTOR signaling and Abeta. Administration of rapamycin in 3XTg-AD mouse model of Alzheimer's disease (AD) rescues cognitive deficits and ameliorates Abeta and Tau pathology. We have dissected the mechanisms by which rapamycin inhibits PS1 expression and Notch1 signaling. Our results demonstrated that rapamycin efficiently suppressed phosphorylation of mTOR (p-mTOR), and decreased expression of PS1-mRNA as well as p-p70S6K1, 4EBP1, PS1, NICD, and Hes1 protein levels. Therefore, rapamycin decreased PS1 protein levels and Notch 1 processing by inhibiting PS1 transcription.

Emerging Alternative Proteinases in APP Metabolism and Alzheimer's Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP.

Processing of amyloid beta precursor protein (APP) into amyloid-beta peptide (Aβ) by β-secretase and γ-secretase complex is at the heart of the pathogenesis of Alzheimer’s disease (AD). Targeting this proteolytic pathway effectively reduces/prevents pathology and cognitive decline in preclinical experimental models of the disease, but therapeutic strategies based on secretase activity modifying drugs have so far failed in clinical trials. Although this may raise some doubts on the relevance of β- and γ-secretases as targets, new APP-cleaving enzymes, including meprin-β, legumain (δ-secretase), rhomboid-like protein-4 (RHBDL4), caspases and membrane-type matrix metalloproteinases (MT-MMPs/η-secretases) have confirmed that APP processing remains a solid mechanism in AD pathophysiology. This review will discuss recent findings on the roles of all these proteinases in the nervous system, and in particular on the roles of MT-MMPs, which are at the crossroads of pathological events involving not only amyloidogenesis, but also inflammation and synaptic dysfunctions. Assessing the potential of these emerging proteinases in the Alzheimer’s field opens up new research prospects to improve our knowledge of fundamental mechanisms of the disease and help us establish new therapeutic strategies.

Peripheral Amyloid Precursor Protein Derivative Expression in Fragile X Syndrome.

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and is associated with increased risk for autism spectrum disorder (ASD), anxiety, ADHD, and epilepsy. While our understanding of FXS pathophysiology has improved, a lack of validated blood-based biomarkers of disease continues to impede bench-to-bedside efforts. To meet this demand, there is a growing effort to discover a reliable biomarker to inform treatment discovery and evaluate treatment target engagement. Such a marker, amyloid-beta precursor protein (APP), has shown potential dysregulation in the absence of fragile X mental retardation protein (FMRP) and may therefore be associated with FXS pathophysiology. While APP is best understood in the context of Alzheimer disease, there is a growing body of evidence suggesting the molecule and its derivatives play a broader role in regulating neuronal hyperexcitability, a well-characterized phenotype in FXS. To evaluate the viability of APP as a peripheral biological marker in FXS, we conducted an exploratory ELISA-based evaluation of plasma APP-related species involving 27 persons with FXS (mean age: 22.0 ± 11.5) and 25 age- and sex-matched persons with neurotypical development (mean age: 21.1 ± 10.7). Peripheral levels of both Aβ(1–40) and Aβ(1–42) were increased, while sAPPα was significantly decreased in persons with FXS as compared to control participants. These results suggest that dysregulated APP processing, with potential preferential β-secretase processing, may be a readily accessible marker of FXS pathophysiology.

SERUM ANALYSIS OF AMYLOID BETA-PROTEIN 1-40 IN HEALTHY SUBJECTS, AUTISTIC CHILDREN AND ALZHEIMER’S PATIENTS

Abstract Amyloid beta-protein^sub 1-40^ (AP40) is a low molecular weight peptide produced throughout life during normal cell metabolism and neurodegenerative diseases. Owing to its neurotrophic and neurotoxic effects, the present study was conducted to evaluate serum levels of AP40 in healthy subjects, autistic children and Alzheimer's disease patients. Serum AP40 was measured by enzyme-linked immunosorbent assay (ELISA). AP40 was significantly higher in normal children compared to normal older controls, in normal children compared to autistic children, and in autistic children compared to Alzheimer's patients (p value was less than 0.05 for all groups). This finding suggests an age-related decline of serum AP40 in normal aging, as well as in autism and Alzheimer's disease. This decline may result from abnormal processing of amyloid beta-protein precursor (APP) during normal aging and age-related diseases such as autism in children and Alzheimer's disease in elderly. Possible explanations for this decline may include age-related increased interactions of AP40 with cytoskeletal proteins for brain tissue deposition, increased serine proteases for APP metabolism or hyperimmune reaction (antibodies to AP40) for removal of circulating AP40. To conclude, the AP40 metabolism declines with normal aging and in addition to its role in Alzheimer's disease this protein might also be a contributing factor in autism. Key Words: Autism; Amyloid-beta protein, Alzheimer's disease; Aging, Neuropathology (ProQuest: ... denotes non-US-ASCII text omitted.) Introduction Accumulation of AP40 occurs in the brain during normal aging but its amount is increased in the brain of patients with Alzheimer's disease (1). In addition to brain, AP40 has been localized outside the brain in skin fibroblasts and biological fluids, including the blood serum. AP40 is well known to exhibit both neurotrophic and neurotoxic effects (2-4), including neurogenic action on neural stem cells (5). Considering these properties, we hypothesized that AP40 might play a pathogenic role in autism. Autism is an early-onset disorder of the developing central nervous system (CNS), manifesting both neurological and behavioral impairments. The disorder causes severe deficits of higher mental functions such as social interaction, language, cognition, communication, and imagination. Autism is the fastest-growing developmental disability today. The disorder affects millions of people worldwide, but very little is known about the etiology and pathogenesis of the disorder. Current theories include genetic factors, immune factors, environmental factors and yet other unidentified factors. The evidence is rapidly accumulating to support hypothesis in autism (6-10). Autoimmunity in autistic children is shown by several autoimmune factors: brain-specific autoantibodies, impaired lymphocyte functions, abnormal cytokine regulation, viral association, linkage of certain immunogenetic factors, and response to immune modulation therapy (6-10). The present study describes results of laboratory analysis of serum AP40, which was found to decline during normal aging, autistic children and Alzheimer's patients. Preliminary findings of this study were presented elsewhere (11). Human Subjects and Methods The study included 53 normal children (age 3-13 yrs), 9 normal adults (age 25-40 yrs), 9 normal aged controls (age 50-80 yrs), 53 autistic children (age 4-12 yrs) and 21 Alzheimer's disease patients (age 60-82 yrs). The clinical diagnosis of autism was made essentially according to the standard DSM-IV criteria of the American Association of Psychiatrists, Washington, DC. Neurologists made the clinical diagnosis of Alzheimer's disease (AD) according to the NINCDS-ADRDA criteria, which also included a 'Mini-Mental State' examination and a two-year downward course of the disease progression. The IRB of Utah State University and the University of Michigan reviewed and approved our research protocol involving the use of human blood samples (6-8). …

Reduction of Liver X Receptor β expression in primary rat neurons by antisense oligodeoxynucleotides decreases secreted amyloid β levels

Ligand-activated Liver X Receptor (LXR) is known to increase cholesterol efflux from cells and reduce the production of amyloid β (Aβ) from amyloid-beta precursor protein (APP). However, little is known about the effects of LXRβ, one subtype of LXR, on endogenous Aβ. In this study, we show that LXRβ inactivation with specific antisense oligodeoxynucleotides (As-ODN) significantly reduced secreted Aβ and decreased mRNA levels of APP751+770, and α-, β-secretase (ADAM10, BACE1) in primary rat neurons. We also show that As-ODN down-regulated the LXR responsive genes ABCA1 and HMG-CoA reductase (HMGCR). These changes are associated with decreased cellular cholesterol levels. The effect of LXRβ inactivation on Aβ levels is likely due to the alteration of cholesterol production and APP processing. Thus, our data suggest that LXRβ has an important function in cholesterol homeostasis and endogenous Aβ maintenance in neurons.

Curcumin Decreases Amyloid-β Peptide Levels by Attenuating the Maturation of Amyloid-β Precursor Protein

Alzheimer disease (AD) is a devastating neurodegenerative disease with no cure. The pathogenesis of AD is believed to be driven primarily by amyloid-beta (Abeta), the principal component of senile plaques. Abeta is an approximately 4-kDa peptide generated via cleavage of the amyloid-beta precursor protein (APP). Curcumin is a compound in the widely used culinary spice, turmeric, which possesses potent and broad biological activities, including anti-inflammatory and antioxidant activities, chemopreventative effects, and effects on protein trafficking. Recent in vivo studies indicate that curcumin is able to reduce Abeta-related pathology in transgenic AD mouse models via unknown molecular mechanisms. Here, we investigated the effects of curcumin on Abeta levels and APP processing in various cell lines and mouse primary cortical neurons. We show for the first time that curcumin potently lowers Abeta levels by attenuating the maturation of APP in the secretory pathway. These data provide a mechanism of action for the ability of curcumin to attenuate amyloid-beta pathology.

Propargylamine Containing Compounds as Modulators of Proteolytic Cleavage of Amyloid Protein Precursor: Involvement of MAPK and PKC Activation

The anti-Parkinsonian, irreversible, selective monoamine oxidase (MAO)-B inhibitors, selegiline (deprenyl, (R)-N-methyl-N-(1-phenylpropan-2-yl) prop-2-yn-1-amine) and rasagiline (Azilect, N-propargyl-1(R)-aminoindan), have been proven to possess neuroprotective/neurorestorative activities in cell cultures and animal models of neurodegenerative diseases. Structure-activity studies provide evidence that neuroprotection is associated with some intrinsic pharmacological action of the propargylamine moiety in these drugs. This indication and recent therapeutic approaches, entailing new drug candidates possessing diverse pharmacological properties and acting on multiple targets, have stimulated the development of two multifunctional chimeric propargylamine-derivatives: 1) ladostigil (TV3326, [(N-propargyl-(3R) 1-(R)-aminoindan-5yl)-ethyl methyl carbamate)], which combines the pharmacophore of rasagiline, with the carbamate moiety of the cholinesterase inhibitor rivastigmine, as a potential treatment for Alzheimer's disease and Lewy body disease; and 2) M30 5-[(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline], where the propargylamine moiety of rasagiline was embedded onto the backbone of the neuroprotective and brain permeable iron chelator 8-hydroxyquinoline-derivative, VK28 as a potential treatment for various neurodegenerative disorders. Both multifunctional propargylamine-derivatives were found to possess neuroprotective and anti-apoptotic properties. An additional and new neuroprotective effect, shared by the propargylamine-derivative compounds, is related to their ability to regulate the processing of amyloid-beta protein precursor (AbetaPP) by the non-amyloidogenic alpha-secretase pathway. This effect was shown to involve activation of p42/44 mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) signaling pathway. This review will summarize and discuss current research, focused on the effect of propargylamine-related derivatives on the proteolytic processing of AbetaPP and signal transduction mechanisms.

Withanolide A and asiatic acid modulate multiple targets associated with amyloid-beta precursor protein processing and amyloid-beta protein clearance.

Alzheimer's disease (AD) is a progressive, neurodegenerative disease histochemically characterized by extracellular deposits of amyloid beta (Abeta) protein and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. AD is considered to be a complex, multifactorial syndrome, with numerous causal factors contributing to its pathogenesis. Thus, for any novel therapeutic molecule to have a "disease-modifying" effect on AD, it must be able to modulate multiple, synergistic targets simultaneously. In this context, we have studied two compounds of plant origin [withanolide A (1) and asiatic acid (2)] for their potential activities against multiple targets associated with Abeta pathways (BACE1, ADAM10, IDE, and NEP). BACE1 is a rate-limiting enzyme in the production of Abeta from amyloid-beta precursor protein (AbetaPP), while ADAM10 is involved in non-amyloidogenic processing of AbetaPP. IDE and NEP are two of the prominent enzymes involved in effectively degrading Abeta. It was found that both 1 and 2 significantly down-regulated BACE1 and also up-regulated ADAM10 in primary rat cortical neurons. In addition, 1 significantly up-regulated IDE levels, which may help in degrading excess Abeta from the AD brain. On the basis of the data obtained, the two multifunctional compounds may prove valuable in developing novel, effective therapeutics for the prevention and treatment of AD-associated amyloid pathology.

The selective β1‐adrenoceptor antagonist nebivolol is a potential oestrogen receptor agonist with neuroprotective abilities

Nebivolol, a selective beta(1)-adrenoceptor antagonist mediating rapid vasodilating effects, is used clinically to treat hypertension. Recently, it was reported that nebivolol also acts as an oestrogen receptor (ER) agonist. To investigate the neuroprotective potential of oestrogens, we assessed the oestrogenic effects of nebivolol in several in vitro neuronal models. Human neuroepithelioma SK-N-MC cells stably transfected with human ER alpha and beta, and mouse N2A neuroblastoma cells expressing human APP695(SWE)[N2Aswe, stably transfected with the Swedish mutation form of the Alzheimer-associated amyloid precursor protein (APPswe, K670M/N671L)] were incubated with different concentrations of nebivolol and 17beta-oestradiol (E2) for 24-48 h. ER activation was detected in a specific reporter assay, and ER-dependent gene expression was measured by quantitative real-time PCR (qRT PCR). Furthermore, cell survival rates were determined, and oxidative stress was induced by hydrogen peroxide and paraquat. Amyloid beta protein precursor (APP) processing was investigated, and the cleavage fragments sAPPalpha and Abeta were quantified via alpha-, beta- and gamma-secretase activity assays. Alterations of secretase expression levels were determined by qRT PCR. Nebivolol induces oestrogen-dependent gene transcription, and protects neuronal cells against oxidative stress even at low and physiological concentrations (10(-8) M). Moreover, nebivolol modulates processing of APP in mouse neuronal N2Aswe cells by increasing alpha-secretase activity, ultimately leading to enhanced release of soluble non-amyloidogenic sAPPalpha. We showed that nebivolol acts as ER agonist in neuronal cell lines, and suggest oestrogen-like neuroprotective effects mediated by nebivolol.

The Pre-Eclampsia Gene STOX1 Controls a Conserved Pathway in Placenta and Brain Upregulated in Late-Onset Alzheimer's Disease

Pre-eclampsia and late-onset Alzheimer's disease (LOAD) share no clinical features. In contrast to these clinical dissimilarities, striking parallels exist between the (epi)genetic features associated with pre-eclampsia and LOAD for the genes located on 10q22. The parallels in identity between the 10q22 genes involved and active in the organs (placenta, brain) primarily affected in the respective diseases led us to explore, if the pre-eclampsia susceptibility gene STOX1 is functionally involved in LOAD. We demonstrate that isoform A of STOX1 is abundantly expressed in the brain, correlates with severity of disease, and selectively transactivates LRRTM3 in neural cells with increased amyloid-beta protein precursor processing. Similar in vitro results were seen in trophoblast. Our data indicate that STOX1 controls a conserved pathway shared between placenta and brain with overexpression in LOAD.

The Syntaxin 5 Isoforms Syx5 and Syx5L have Distinct Effects on the Processing of β-amyloid Precursor Protein

In this study, we examined the interaction of Syntaxin 5L (Syx5L), a Syx5 isoform that has an N-terminal extension containing a di-arginine ER-retrieval motif, with presenilin (PS) and its effects on the processing of beta-amyloid precursor protein (betaAPP). Similar to Syx5, Syx5L bound to PS1 holoprotein but not to its N- or C-terminal fragments. Unlike Syx5, Syx5L overexpression did not cause marked accumulation of intracellular betaAPP holoprotein, and did not inhibit amyloid beta peptide (Abeta) secretion. Analyses using deletion mutants of Syx5L revealed that, in addition to the difference in the intracellular localization between the isoforms, the presence of the N-terminal extension in Syx5L was critical for suppressing its inhibition of betaAPP processing. Treatment of cells that overexpressed Syx5L with brefeldin A, an inhibitor of transport from the ER to the Golgi compartments, resulted in substantial accumulation of intracellular betaAPP holoprotein and reduction in the secretion of Abeta. Although Syx5 and Syx5L share lengthy regions of amino acid identity, they appear to play distinct roles in modulating the metabolism and trafficking of betaAPP in the early secretory compartment.

Concentrations of beta-amyloid precursor protein processing products in cerebrospinal fluid of patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders with heterogeneous clinical presentation but common neuropathological characteristics and pathophysiological substrates, which led to the view of ALS and FTLD representing two manifestations of a clinicopathological spectrum. For both diseases, changes in metabolism of beta-amyloid precursor protein (APP) are reported. In a pilot study, we analyzed cerebrospinal fluid from patients of the ALS-FTLD spectrum for APP processing products. ALS patients show elevated absolute levels of soluble APP and a shift towards the nonamyloidogenic APP processing pathway in contrast to patients with FTLD or ALS + FTLD. Changes in Abeta pattern could be described, allowing separation of patients with pure FTLD from ALS + FTLD. Combination of sAPP and Abeta values improves group differentiation. These findings may provide information on pathophysiological processes in the ALS-FTLD disease spectrum and could have impact in neurochemical diagnosis. We propose to expand this study to larger patient groups comprising followed up cases with known neuropathology.

TDP-43 and beta-amyloid precursor protein processing products in cerebrospinal fluid of patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration

TDP-43 and beta-amyloid precursor protein processing products in cerebrospinal fluid of patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration

Expanding functions of lipoprotein receptors

Lipoprotein receptors are evolutionarily ancient proteins that are expressed on the surface of many cell types. Beginning with the appearance of the first primitive multicellular organisms, several structurally and functionally distinct families of lipoprotein receptors evolved. Originally, these cell surface proteins were thought to merely mediate the traffic of lipids and nutrients between cells and, in some cases, by functioning as scavenger receptors, remove other kinds of macromolecules, such as proteases and protease inhibitors from the extracellular space and the cell surface. Over the last decade, this picture has fundamentally changed. We now appreciate that many of these receptors are not mere cargo transporters; they are deeply embedded in the machinery by which cells communicate with each other. By physically interacting and coevolving with fundamental signaling pathways, lipoprotein receptors have occupied essential and surprisingly diverse functions that are indispensable for integrating the complex web of cellular signal input during development and in differentiated tissues.

Formation of amyloid-β oligomers in brain vascular smooth muscle cells transiently exposed to iron-induced oxidative stress

Vascular smooth muscle cells are involved in deposition of amyloid in brain blood vessels. Accumulation of amyloid-beta peptide (Abeta) in cultured brain vascular smooth muscle cells that overexpress human amyloid-beta precursor protein (APP) Swedish, is strongly enhanced by exposure to iron ions. We studied cellular accumulation of Abeta and APP processing in vascular smooth muscle cells during recovery after exposure to ferrous ions using cells cultured from Tg2576 mice. The treatment with ferrous ions for 24 and 48 h significantly increased the intracellular levels of ferric, but not ferrous iron. The treatment led to cellular accumulation of C-terminal fragments of APP and to a decreased secretion of APP, Abeta1-40, and Abeta1-42, all of which were quickly normalized in iron-free culture conditions. These effects of iron were neutralized by alpha-tocopherol, suggesting the role of oxygen reactive species in altered APP processing. Formation of abundant Abeta oligomers, mainly Abeta1-40 tetramers and pentamers, were detected in iron-treated cells, particularly during subsequent culture in iron-free media for up to 72 h. The data suggest that transient increases in local availability of iron in brain blood vessel walls in vivo, e.g., after microhemorrhages, may trigger Abeta oligomerization.