Changes In Amyloid Precursor Protein Research Articles

Amyloid Precursor Protein Changes Arrangement in a Membrane and Its Structure Depending on the Cholesterol Content.

One of the hallmarks of Alzheimer's disease (AD) is the accumulation of amyloid beta (Aβ) peptides in the brain. The processing of amyloid precursor protein (APP) into Aβ is dependent on the location of APP in the membrane, membrane lipid composition and, possibly, presence of lipid rafts. In this study, we used atomic force microscopy (AFM) to investigate the interaction between transmembrane fragment APP672-726 (corresponding to Aβ1-55) and its amyloidogenic mutant L723P with membranes combining liquid-ordered and liquid-disordered lipid phases. Our results demonstrated that most of the APP672-726 is located either in the liquid-disordered phase or at the boundary between ordered and disordered phases, and hardly ever in rafts. We did not notice any major changes in the domain structure induced by APP672-726. In membranes without cholesterol APP672-726, and especially its amyloidogenic mutant L723P formed annular structures and clusters rising above the membrane. Presence of cholesterol led to the appearance of concave membrane regions up to 2 nm in depth that were deeper for wild type APP672-726. Thus, membrane cholesterol regulates changes in membrane structure and permeability induced by APP that might be connected with further formation of membrane pores.

Intraneuronal β-Amyloid Accumulation: Aging HIV-1 Human and HIV-1 Transgenic Rat Brain.

The prevalence of HIV-1 associated neurocognitive disorders (HAND) is significantly greater in older, relative to younger, HIV-1 seropositive individuals; the neural pathogenesis of HAND in older HIV-1 seropositive individuals, however, remains elusive. To address this knowledge gap, abnormal protein aggregates (i.e., β-amyloid) were investigated in the brains of aging (>12 months of age) HIV-1 transgenic (Tg) rats. In aging HIV-1 Tg rats, double immunohistochemistry staining revealed abnormal intraneuronal β-amyloid accumulation in the prefrontal cortex (PFC) and hippocampus, relative to F344/N control rats. Notably, in HIV-1 Tg animals, increased β-amyloid accumulation occurred in the absence of any genotypic changes in amyloid precursor protein (APP). Furthermore, no clear amyloid plaque deposition was observed in HIV-1 Tg animals. Critically, β-amyloid was co-localized with neurons in the cortex and hippocampus, supporting a potential mechanism underlying synaptic dysfunction in the HIV-1 Tg rat. Consistent with these neuropathological findings, HIV-1 Tg rats exhibited prominent alterations in the progression of temporal processing relative to control animals; temporal processing relies, at least in part, on the integrity of the PFC and hippocampus. In addition, in post-mortem HIV-1 seropositive individuals with HAND, intraneuronal β-amyloid accumulation was observed in the dorsolateral PFC and hippocampal dentate gyrus. Consistent with observations in the HIV-1 Tg rat, no amyloid plaques were found in these post-mortem HIV-1 seropositive individuals with HAND. Collectively, intraneuronal β-amyloid aggregation observed in the PFC and hippocampus of HIV-1 Tg rats supports a potential factor underlying HIV-1 associated synaptodendritic damage. Further, the HIV-1 Tg rat provides a biological system to model HAND in older HIV-1 seropositive individuals.

Decrease in 130 kDa- amyloid protein precursor protein (APP) and APP protein ratio in schizophrenia platelets

Cognitive dysfunction is common among people with schizophrenia. The molecular substrates underlying this remain poorly understood. To address this, we analyzed changes in amyloid precursor protein (APP) in platelets of people with acute schizophrenia (n=24) and control subjects (n=20) by ECL-immunoblotting. APP bands corresponding to molecular masses of ∼130, ∼110 and ∼100 kDa, and the APP ratio (APPr: highest APP molecular mass vs lowest APP molecular mass bands) were quantified. The intensity of 130 kDa-APP and the APPr were significantly reduced in schizophrenia patients compared to control subjects. The age-associated decreases in the 130 kDa, ∼110 kDa proteins and APPr were present in patients, but not controls. Our results confirm peripheral APP metabolism is altered in people with schizophrenia. Further work is now warranted on a larger sample of diseased subjects with detailed cognitive assessment to determine the APP role in cognitive processing in schizophrenia, how it is related to severity and disease progression, as well as outcomes.

Amyloid-β, tau, and the cholinergic system in Alzheimer’s disease: seeking direction in a tangle of clues

The link between histopathological hallmarks of Alzheimer's disease (AD), i.e. amyloid plaques, and neurofibrillary tangles, and AD-associated cognitive impairment, has long been established. However, the introduction of interactions between amyloid-beta (Aβ) as well as hyperphosphorylated tau, and the cholinergic system to the territory of descriptive neuropathology has drastically changed this field by adding the theory of synaptic neurotransmission to the toxic pas de deux in AD. Accumulating data show that a multitarget approach involving all amyloid, tau, and cholinergic hypotheses could better explain the evolution of events happening in AD. Various species of both Aβ and tau could be traced in cholinergic neurons of the basal forebrain system early in the course of the disease. These molecules induce degeneration in the neurons of this system. Reciprocally, aberrant cholinergic system modulation promotes changes in amyloid precursor protein (APP) metabolism and tau phosphorylation, resulting in neurotoxicity, neuroinflammation, and neuronal death. Altogether, these changes may better correlate with the clinical findings and cognitive impairment detected in AD patients. Failure of several of Aβ- and tau-related therapies further highlights the need for special attention to molecules that target all of these mentioned pathologic changes. Another noteworthy fact here is that none of the popular hypotheses of AD such as amyloidopathy or tauopathy seem to be responsible for the changes observed in AD alone. Thus, the main culprit should be sought higher in the stream somewhere in APP metabolism or Wnt signaling in the cholinergic system of the basal forebrain. Future studies should target these pathological events.

Chapter 13 - Alzheimer's disease

Alzheimer's disease (AD) dementia refers to a particular onset and course of cognitive and functional decline associated with age together with a particular neuropathology. It was first described by Alois Alzheimer in 1906 about a patient whom he first encountered in 1901. Modern clinical diagnostic criteria have been developed, and criteria have also been proposed to recognize preclinical (or presymptomatic) stages of the disease with the use of biomarkers. The primary neuropathology was described by Alzheimer, and in the mid-1980s subsequently evolved into a more specific neuropathologic definition that recognizes the comorbid neuropathologies that frequently contribute to clinical dementia. Alzheimer's disease is now the most common form of neurodegenerative dementia in the United States with a disproportionate disease burden in minority populations. Deficits in the ability to encode and store new memories characterizes the initial stages of the disease. Subsequent progressive changes in cognition and behavior accompany the later stages. Changes in amyloid precursor protein (APP) cleavage and production of the APP fragment beta-amyloid (Aβ) along with hyperphosphorylated tau protein aggregation coalesce to cause reduction in synaptic strength, synaptic loss, and neurodegeneration. Metabolic, vascular, and inflammatory changes, as well as comorbid pathologies are key components of the disease process. Symptomatic treatment offers a modest, clinically measurable effect in cognition, but disease-modifying therapies are desperately needed.

Moderate blast exposure alters gene expression and levels of amyloid precursor protein.

Objective:To explore gene expression after moderate blast exposure (vs baseline) and proteomic changes after moderate- (vs low-) blast exposure.Methods:Military personnel (N = 69) donated blood for quantification of protein level, and peak pressure exposures were detected by helmet sensors before and during a blast training program (10 days total). On day 7, some participants (n = 29) sustained a moderate blast (mean peak pressure = 7.9 psi) and were matched to participants with no/low-blast exposure during the training (n = 40). PAXgene tubes were collected from one training site at baseline and day 10; RNA-sequencing day 10 expression was compared with each participant's own baseline samples to identify genes and pathways differentially expressed in moderate blast-exposed participants. Changes in amyloid precursor protein (APP) from baseline to the day of blast and following 2 days were evaluated. Symptoms were assessed using a self-reported form.Results:We identified 1,803 differentially expressed genes after moderate blast exposure; the most altered network was APP. Significantly reduced levels of peripheral APP were detected the day after the moderate blast exposure and the following day. Protein concentrations correlated with the magnitude of the moderate blast exposure on days 8 and 9. APP concentrations returned to baseline levels 3 days following the blast, likely due to increases in the genetic expression of APP. Onset of concentration problems and headaches occurred after moderate blast.Conclusions:Moderate blast exposure results in a signature biological profile that includes acute APP reductions, followed by genetic expression increases and normalization of APP levels; these changes likely influence neuronal recovery.

Sortilin-Related Receptor Expression in Human Neural Stem Cells Derived from Alzheimer's Disease Patients Carrying the APOE Epsilon 4 Allele.

Alzheimer's disease (AD) is the most common form of dementia in the elderly; important risk factors are old age and inheritance of the apolipoprotein E4 (APOE4) allele. Changes in amyloid precursor protein (APP) binding, trafficking, and sorting may be important AD causative factors. Secretase-mediated APP cleavage produces neurotoxic amyloid-beta (Aβ) peptides, which form lethal deposits in the brain. In vivo and in vitro studies have implicated sortilin-related receptor (SORL1) as an important factor in APP trafficking and processing. Recent in vitro evidence has associated the APOE4 allele and alterations in the SORL1 pathway with AD development and progression. Here, we analyzed SORL1 expression in neural stem cells (NSCs) from AD patients carrying null, one, or two copies of the APOE4 allele. We show reduced SORL1 expression only in NSCs of a patient carrying two copies of APOE4 allele with increased Aβ/SORL1 localization along the degenerated neurites. Interestingly, SORL1 binding to APP was largely compromised; this could be almost completely reversed by γ-secretase (but not β-secretase) inhibitor treatment. These findings may yield new insights into the complex interplay of SORL1 and AD pathology and point to NSCs as a valuable tool to address unsolved AD-related questions in vitro.

1950 MHz radiofrequency electromagnetic fields do not aggravate memory deficits in 5xFAD mice.

The increased use of mobile phones has generated public concern about the impact of radiofrequency electromagnetic fields (RF‐EMF) on health. In the present study, we investigated whether RF‐EMFs induce molecular changes in amyloid precursor protein (APP) processing and amyloid beta (Aβ)‐related memory impairment in the 5xFAD mouse, which is a widely used amyloid animal model. The 5xFAD mice at the age of 1.5 months were assigned to two groups (RF‐EMF‐ and sham‐exposed groups, eight mice per group). The RF‐EMF group was placed in a reverberation chamber and exposed to 1950 MHz electromagnetic fields for 3 months (SAR 5 W/kg, 2 h/day, 5 days/week). The Y‐maze, Morris water maze, and novel object recognition memory test were used to evaluate spatial and non‐spatial memory following 3‐month RF‐EMF exposure. Furthermore, Aβ deposition and APP and carboxyl‐terminal fragment β (CTFβ) levels were evaluated in the hippocampus and cortex of 5xFAD mice, and plasma levels of Aβ peptides were also investigated. In behavioral tests, mice that were exposed to RF‐EMF for 3 months did not exhibit differences in spatial and non‐spatial memory compared to the sham‐exposed group, and no apparent change was evident in locomotor activity. Consistent with behavioral data, RF‐EMF did not alter APP and CTFβ levels or Aβ deposition in the brains of the 5xFAD mice. These findings indicate that 3‐month RF‐EMF exposure did not affect Aβ‐related memory impairment or Aβ accumulation in the 5xFAD Alzheimer's disease model. Bioelectromagnetics. 37:391–399, 2016. © 2016 The Authors Bioelectromagnetics published by Wiley Periodicals, Inc. on behalf of Bioelectromagnetics Society.

Cell biology and the "real world".

Cell biology and the "real world".

Retromer disruption promotes amyloidogenic APP processing

Retromer deficiency has been implicated in sporadic AD and animals deficient in retromer components exhibit pronounced neurodegeneration. Because retromer performs retrograde transport from the endosome to the Golgi apparatus and neuronal Aβ is found in late endosomal compartments, we speculated that retromer malfunction might enhance amyloidogenic APP processing by promoting interactions between APP and secretase enzymes in late endosomes. We have evaluated changes in amyloid precursor protein (APP) processing and trafficking as a result of disrupted retromer activity by knockdown of Vps35, a vacuolar sorting protein that is an essential component of the retromer complex. Knocking down retromer activity produced no change in the quantity or cellular distribution of total cellular APP and had no affect on internalization of cell-surface APP. Retromer deficiency did, however, increase the ratio of secreted Aβ42:Aβ40 in HEK-293 cells over-expressing APP 695, due primarily to a decrease in Aβ40 secretion. Recent studies suggest that the retromer-trafficked protein, Wntless, is secreted at the synapse in exosome vesicles and that these same vesicles contain Aβ. We therefore hypothesized that retromer deficiency may be associated with altered exosomal secretion of APP and/or secretase fragments. Holo-APP, Presenilin and APP C-terminal fragments were detected in exosomal vesicles secreted from HEK-293 cells. Levels of total APP C-terminal fragments were significantly increased in exosomes secreted by retromer deficient cells. These data suggest that reduced retromer activity can mimic the effects of familial AD Presenilin mutations on APP processing and promote export of amyloidogenic APP derivatives.

P1-023: Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer’s disease amyloid neuropathology by calorie restriction

In previous studies we reported that calorie restriction (CR)–treatment reduces Alzheimer's disease (AD)–type β–amyloid (Aβ) neuropathology in the brain of the Tg2576 mouse model of AD. The intent of the present study is to evaluate a possible mechanism through which CR may prevent AD–type neuropathology, specifically the involvement of the nicotinamide adenine dinucleotide (NAD)+–dependent SIRT1 mediated deacetylase activity, which has been identified to be a key regulator in the lifespan extending effects of CR in a number of species. In this study we report that CR treatment for 6 months leads to significant increase in SIRT1 protein and enhanced NAD+ /nicotinamide (NAM) ratio in the brain of the 10–month old Tg2576 mice relative to the age– and gender– matched ad–libitum fed control Tg2576 mice. We demonstrate that the predicted changes in Aβ peptide content in the brain by CR can be reproduced in embryonic Tg2576 neurons in vitro by manipulating cellular SIRT1 expression or by treatment with the SIRT1 activators NAD+ or resveratrol. Our studies, for the first time, directly link changes in neuronal SIRT1 expression/activity to changes in amyloid precursor protein (APP) processing involved in Aβ generation, specifically to increase in non–amyloidogenic α–secretase activity. The present study strongly points to SIRT1 activation and enhancement of the NAD+/NAM ratio in the brain as potential novel attractive pharmacological strategy for AD prevention or treatment.

P1-231 Post-injury increases in NFKB precede changes in amyloid precursor protein and amyloid beta following traumatic brain injury

P1-231 Post-injury increases in NFKB precede changes in amyloid precursor protein and amyloid beta following traumatic brain injury

Changes in amyloid precursor protein and apolipoprotein E immunoreactivity following ischemic brain injury in rat with long-term survival: influence of idebenone treatment

We observed in extra- and intracellular space accumulation of different fragments of amyloid precursor protein (APP) and apolipoprotein E (Apo E) in rat brain after cardiac arrest with long-term survival. Idebenone treatment did not affect APP and Apo E alterations in this condition.