Alzheimer's amyloid-β and tau protein accumulation is associated with decreased expression of the LDL receptor-associated protein in human brain tissue.

Introduction: One of the major neuropathological features of Alzheimer's disease (AD) is the accumulation of amyloid-β (Aβ) protein in the brain. Evidence suggests that the low-density lipoprotein receptor-associated protein (RAP) binds strongly to Aβ and enhances its cellular uptake and that decreased RAP expression correlates with increased Aβ production in animal models of AD.

Methods: The current study examined whether RAP levels change in AD human brain tissue and whether they are related to the amount of AD pathology.

Knockout of Amyloid β Protein Precursor (APP) Expression Alters Synaptogenesis, Neurite Branching and Axonal Morphology of Hippocampal Neurons.

The function of the β-A4 amyloid protein precursor (APP) of Alzheimer's disease (AD) remains unclear. APP has a number of putative roles in neuronal differentiation, survival, synaptogenesis and cell adhesion. In this study, we examined the development of axons, dendrites and synapses in cultures of hippocampus neutrons derived from APP knockout (KO) mice.

Peripheral treatment with enoxaparin exacerbates amyloid plaque pathology in Tg2576 mice.

Alzheimer's disease (AD) is a complex, progressive neurological disorder characterized by the formation of extracellular amyloid plaques composed of β-amyloid protein (Aβ), the key component in pathogenesis of AD. Peripheral administration of enoxaparin (ENO) reportedly reduces the level of Aβ and the amyloid plaques in the cortex of amyloid precursor protein (APP) transgenic mice. However, the exact mechanism of these effects is unclear.

N-terminal domain of Bothrops asper Myotoxin II Enhances the Activity of Endothelin Converting Enzyme-1 and Neprilysin.

Neprilysin (NEP) and endothelin converting enzyme-1 (ECE-1) are two enzymes that degrade amyloid beta in the brain. Currently there are no molecules to stimulate the activity of these enzymes. Here we report, the discovery and characterisation of a peptide referred to as K49-P1-20, from the venom of Bothrops asper which directly enhances the activity of both ECE-1 and NEP.

Do Microglia Default on Network Maintenance in Alzheimer's Disease?

Although the cause of Alzheimer's disease (AD) remains unknown, a number of new findings suggest that the immune system may play a critical role in the early stages of the disease. Genome-wide association studies have identified a wide array of risk-associated genes for AD, many of which are associated with abnormal functioning of immune cells. Microglia are the brain's immune cells.

Neurogenin 2 mediates amyloid-β precursor protein-stimulated neurogenesis.

Amyloid-β precursor protein (APP) is well studied for its role in Alzheimer disease, although its normal function remains uncertain. It has been reported that APP stimulates the proliferation and neuronal differentiation of neural stem/progenitor cells (NSPCs). In this study we examined the role of APP in NSPC differentiation.

The N-terminal fragment of the β-amyloid precursor protein of Alzheimer's disease (N-APP) binds to phosphoinositide-rich domains on the surface of hippocampal neurons.

The function of the β-amyloid precursor protein (APP) of Alzheimer's disease is poorly understood. The secreted ectodomain fragment of APP (sAPPα) can be readily cleaved to produce a small N-terminal fragment (N-APP) that contains heparin-binding and metal-binding domains and that has been found to have biological activity. In the present study, we examined whether N-APP can bind to lipids.

Insights into the physiological function of the β-amyloid precursor protein: beyond Alzheimer's disease.

The β-amyloid precursor protein (APP) has been extensively studied for its role as the precursor of the β-amyloid protein (Aβ) of Alzheimer's disease. However, the normal function of APP remains largely unknown. This article reviews studies on the structure, expression and post-translational processing of APP, as well as studies on the effects of APP in vitro and in vivo.

β-Amyloid precursor protein: function in stem cell development and Alzheimer's disease brain.

Stem cell therapy may be a suitable approach for the treatment of many neurodegenerative diseases. However, one major impediment to the development of successful cell-based therapies is our limited understanding of the mechanisms that instruct neural stem cell behaviour, such as proliferation and cell fate specification. The β-amyloid precursor protein (APP) of Alzheimer's disease (AD) may play an important role in neural stem cell proliferation and differentiation.

Role of cystatin C in amyloid precursor protein-induced proliferation of neural stem/progenitor cells.

The amyloid precursor protein (APP) is well studied for its role in Alzheimer disease. However, little is known about its normal function. In this study, we examined the role of APP in neural stem/progenitor cell (NSPC) proliferation.

Mechanisms of transthyretin aggregation and toxicity.

Amyloidoses are characterised by the deposition of insoluble protein that occurs in the extracellular compartment of various tissues. One form of amyloidosis is caused by transthyretin (TTR) misfolding and deposition in target tissues. It is clear that many amyloidoses share common features of fibrillogenesis and toxicity.

Size and sulfation are critical for the effect of heparin on APP processing and Aβ production.

Alzheimer's disease is associated with abnormal accumulation of Aβ, which is produced from the β-amyloid precursor protein (APP) by the β-site APP-cleaving enzyme (BACE1) and γ-secretase. Our previous studies showed that heparin can decrease APP processing by decreasing the levels of BACE1 and ADAM10. In this study, we examined the effects of glycosaminoglycans (GAGs) on APP processing and Aβ production with the aim of understanding the specificity of the effects.

STIM1 is necessary for store-operated calcium entry in turning growth cones.

Coordinated calcium signalling is vital for neuronal growth cone function and axon pathfinding. Although store-operated calcium entry (SOCE) has been suggested to be an important source of calcium in growth cone navigation, the mechanisms that regulate calcium signalling, particularly the regulation of internal calcium stores within growth cones, are yet to be fully determined. Stromal Interaction Molecule 1 (STIM1) is a calcium-sensing protein localized in the endoplasmic reticulum membrane that interacts with Orai proteins in the plasma membrane to initiate SOCE and refilling of intracellular calcium stores.

Dysregulation of Ca2+ homeostasis in Alzheimer's disease: role in acetylcholinesterase production and AMPA receptor internalization.

Amyloid-β (Aβ)-induced Ca(2+) influx into neurons has been well described since it was first reported almost 20 years ago. Ca(2+) influx can disrupt mechanisms of long-term potentiation and long-term depression and increase neuronal susceptibility to excitotoxicity. Our studies show that Aβ also causes an increase in acetylcholinesterase (AChE) levels and induces AMPA receptor internalization through Ca(2+)-dependent mechanisms.

Characterization of early stage intermediates in the nucleation phase of Aβ aggregation.

Alzheimer's disease (AD) is a common form of dementia, which is characterized by the presence of extracellular amyloid plaques comprising the amyloid β peptide (Aβ). Although the mechanism underlying AD pathogenesis remains elusive, accumulating evidence suggests that the process of amyloid fibril formation is a surface-mediated event, which plays an important role in AD onset and progression. In this study, the mechanism of Aβ aggregation on hydrophobic surfaces was investigated with dual polarization interferometry (DPI), which provides real-time information on early stages of the aggregation process.

Revisiting the Role of Acetylcholinesterase in Alzheimer's Disease: Cross-Talk with P-tau and β-Amyloid.

A common feature in the Alzheimer's disease (AD) brain is the presence of acetylcholinesterase (AChE) which is commonly associated with β-amyloid plaques and neurofibrillary tangles (NFT). Although our understanding of the relationship between AChE and the pathological features of AD is incomplete, increasing evidence suggests that both β-amyloid protein (Aβ) and abnormally hyperphosphorylated tau (P-tau) can influence AChE expression. We also review recent findings which suggest the possible role of AChE in the development of a vicious cycle of Aβ and P-tau dysregulation and discuss the limited and temporary effect of therapeutic intervention with AChE inhibitors.

Neurodegeneration in familial amyloidotic polyneuropathy.

Familial amyloid polyneuropathies (FAP) constitute a group of inherited amyloidoses that affect peripheral nerves. One common form of FAP is caused by transthyretin (TTR) misfolding and deposition in the peripheral nervous system, leading to neuronal toxicity and death. The molecular mechanisms responsible for this toxicity are unclear; however, there is good biochemical and histopathological evidence that the toxicity of TTR mutations is correlated to their aggregation state.

Effects of heparin and enoxaparin on APP processing and Aβ production in primary cortical neurons from Tg2576 mice.

Background: Alzheimer's disease (AD) is caused by accumulation of Aβ, which is produced through sequential cleavage of β-amyloid precursor protein (APP) by the β-site APP cleaving enzyme (BACE1) and γ-secretase. Enoxaparin, a low molecular weight form of the glycosaminoglycan (GAG) heparin, has been reported to lower Aβ plaque deposition and improve cognitive function in AD transgenic mice.

Methodology/principal Findings: We examined whether heparin and enoxaparin influence APP processing and inhibit Aβ production in primary cortical cell cultures.

Surface plasmon resonance spectroscopy: a new lead in studying the membrane binding of amyloidogenic transthyretin.

Surface plasmon resonance (SPR) employs the optical principle of SPR to measure changes in mass on a sensor chip surface in real time. Surface chemistry has been developed which enables the immoblization of lipid bilayers and determination of protein-membrane interactions in real time. In the last decade, the plasma membrane has been demonstrated to play an important role in amyloidogenesis and cytotoxicity induced by amyloidogenic proteins.

Altered expression of brain acetylcholinesterase in FTDP-17 human tau transgenic mice.

Pathological hyperphosphorylation and aggregation of the tau protein is associated with dementia and can be the central cause of neurodegeneration. Here, we examined potential alterations in the level of the cholinergic enzyme acetylcholinesterase (AChE) in the brain of transgenic mice (Tg-VLW) expressing human tau mutations. Overexpression of mutant hyperphosphorylated tau (P-tau) led to an increase in the activity of AChE in the brain of Tg-VLW mice, paralleled by an increase in AChE protein and transcripts; whereas the levels of the enzyme choline acetyltransferase remained unaffected.

TRPM8 and Nav1.8 sodium channels are required for transthyretin-induced calcium influx in growth cones of small-diameter TrkA-positive sensory neurons.

Background: Familial amyloidotic polyneuropathy (FAP) is a peripheral neuropathy caused by the extracellular accumulation and deposition of insoluble transthyretin (TTR) aggregates. However the molecular mechanism that underlies TTR toxicity in peripheral nerves is unclear. Previous studies have suggested that amyloidogenic proteins can aggregate into oligomers which disrupt intracellular calcium homeostasis by increasing the permeability of the plasma membrane to extracellular calcium.

Astrocytes in Alzheimer's disease: emerging roles in calcium dysregulation and synaptic plasticity.

Alzheimer's disease (AD) is caused by the accumulation of amyloid-β (Aβ), which induces progressive decline in learning, memory, and other cognitive functions. Aβ is a neurotoxic protein that disrupts calcium signaling in neurons and alters synaptic plasticity. These effects lead to loss of synapses, neural network dysfunction, and inactivation of neuronal signaling.