Concept: Amyloid precursor protein
- Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)
- Published about 4 years ago
The genetic predispositions which describe a diagnosis of familial Alzheimer’s disease can be considered as cornerstones of the amyloid cascade hypothesis. Essentially they place the expression and metabolism of the amyloid precursor protein as the main tenet of disease aetiology. However, we do not know the cause of Alzheimer’s disease and environmental factors may yet be shown to contribute towards its onset and progression. One such environmental factor is human exposure to aluminium and aluminium has been shown to be present in brain tissue in sporadic Alzheimer’s disease. We have made the first ever measurements of aluminium in brain tissue from 12 donors diagnosed with familial Alzheimer’s disease. The concentrations of aluminium were extremely high, for example, there were values in excess of 10μg/g tissue dry wt. in 5 of the 12 individuals. Overall, the concentrations were higher than all previous measurements of brain aluminium except cases of known aluminium-induced encephalopathy. We have supported our quantitative analyses using a novel method of aluminium-selective fluorescence microscopy to visualise aluminium in all lobes of every brain investigated. The unique quantitative data and the stunning images of aluminium in familial Alzheimer’s disease brain tissue raise the spectre of aluminium’s role in this devastating disease.
Presenilins (PSs) are the catalytic core of gamma-secretase complex. However, the mechanism of FAD-associated PS mutations in AD pathogenesis still remains elusive. Here we review the general biology and mechanism of gamma-secretase and focus on the catalytic components – presenilins and their biological functions and contributions to the AD pathogenesis. The functions of presenilins are divided into gamma-secretase dependent and gamma-secretase independent ones. The gamma-secretase dependent functions of presenilins are exemplified by the sequential cleavages in the processing of APP and Notch; the gamma-secretase independent functions of presenilins include stabilizing beta-catenin in Wnt signaling pathway, regulating calcium homeostasis and their interaction with synaptic transmission.
β-Secretase 1 (BACE1) is a key enzyme in Alzheimer’s disease pathogenesis that catalyses the amyloidogenic cleavage of amyloid precursor protein (APP). Recently, global Bace1 deletion was shown to protect against diet-induced obesity and diabetes, suggesting that BACE1 is a potential regulator of glucose homeostasis. Here, we investigated whether increased neuronal BACE1 is sufficient to alter systemic glucose metabolism, using a neuron-specific human BACE1 knockin mouse model (PLB4).
In the present study, we tested whether the volatile metabolome was altered by mutations of the Alzheimer’s disease (AD)-implicated amyloid precursor protein gene (APP) and comprehensively examined urinary volatiles that may potentially serve as candidate biomarkers of AD. Establishing additional biomarkers in screening populations for AD will provide enhanced diagnostic specificity and will be critical in evaluating disease-modifying therapies. Having strong evidence of gross changes in the volatile metabolome of one line of APP mice, we utilized three unique mouse lines which over-express human mutations of the APP gene and their respective non-transgenic litter-mates (NTg). Head-space gas chromatography/mass spectrometry (GC/MS) of urinary volatiles uncovered several aberrant chromatographic peak responses. We later employed linear discrimination analysis and found that the GC/MS peak responses provide accurate (>84%) genotype classification of urinary samples. These initial data in animal models show that mutant APP gene expression entails a uniquely identifiable urinary odor, which if uncovered in clinical AD populations, may serve as an additional biomarker for the disease.
- Proceedings of the National Academy of Sciences of the United States of America
- Published almost 4 years ago
Presenilin 1 (PS1), the catalytic subunit of the γ-secretase complex, cleaves βCTF to produce Aβ. We have shown that PS1 regulates Aβ levels by a unique bifunctional mechanism. In addition to its known role as the catalytic subunit of the γ-secretase complex, selective phosphorylation of PS1 on Ser367 decreases Aβ levels by increasing βCTF degradation through autophagy. Here, we report the molecular mechanism by which PS1 modulates βCTF degradation. We show that PS1 phosphorylated at Ser367, but not nonphosphorylated PS1, interacts with Annexin A2, which, in turn, interacts with the lysosomal N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) Vamp8. Annexin A2 facilitates the binding of Vamp8 to the autophagosomal SNARE Syntaxin 17 to modulate the fusion of autophagosomes with lysosomes. Thus, PS1 phosphorylated at Ser367 has an antiamyloidogenic function, promoting autophagosome-lysosome fusion and increasing βCTF degradation. Drugs designed to increase the level of PS1 phosphorylated at Ser367 should be useful in the treatment of Alzheimer’s disease.
- Proceedings of the National Academy of Sciences of the United States of America
- Published almost 4 years ago
Alzheimer’s disease (AD) is characterized by accumulation of the β-amyloid peptide (Aβ), which is generated through sequential proteolysis of the amyloid precursor protein (APP), first by the action of β-secretase, generating the β-C-terminal fragment (βCTF), and then by the Presenilin 1 (PS1) enzyme in the γ-secretase complex, generating Aβ. γ-Secretase is an intramembranous protein complex composed of Aph1, Pen2, Nicastrin, and Presenilin 1. Although it has a central role in the pathogenesis of AD, knowledge of the mechanisms that regulate PS1 function is limited. Here, we show that phosphorylation of PS1 at Ser367 does not affect γ-secretase activity, but has a dramatic effect on Aβ levels in vivo. We identified CK1γ2 as the endogenous kinase responsible for the phosphorylation of PS1 at Ser367. Inhibition of CK1γ leads to a decrease in PS1 Ser367 phosphorylation and an increase in Aβ levels in cultured cells. Transgenic mice in which Ser367 of PS1 was mutated to Ala, show dramatic increases in Aβ peptide and in βCTF levels in vivo. Finally, we show that this mutation impairs the autophagic degradation of βCTF, resulting in its accumulation and increased levels of Aβ peptide and plaque load in the brain. Our results demonstrate that PS1 regulates Aβ levels by a unique bifunctional mechanism. In addition to its known role as the catalytic subunit of the γ-secretase complex, selective phosphorylation of PS1 on Ser367 also decreases Aβ levels by increasing βCTF degradation through autophagy. Elucidation of the mechanism by which PS1 regulates βCTF degradation may aid in the development of potential therapies for Alzheimer’s disease.
β-Amyloid (Aβ) peptides are thought to be critically involved in the etiology of Alzheimer’s disease (AD). The aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of Aβ, and BACE1 inhibition is thus an attractive target for the treatment of AD. We show that verubecestat (MK-8931) is a potent, selective, structurally unique BACE1 inhibitor that reduced plasma, cerebrospinal fluid (CSF), and brain concentrations of Aβ40, Aβ42, and sAPPβ (a direct product of BACE1 enzymatic activity) after acute and chronic administration to rats and monkeys. Chronic treatment of rats and monkeys with verubecestat achieved exposures >40-fold higher than those being tested in clinical trials in AD patients yet did not elicit many of the adverse effects previously attributed to BACE inhibition, such as reduced nerve myelination, neurodegeneration, altered glucose homeostasis, or hepatotoxicity. Fur hypopigmentation was observed in rabbits and mice but not in monkeys. Single and multiple doses were generally well tolerated and produced reductions in Aβ40, Aβ42, and sAPPβ in the CSF of both healthy human subjects and AD patients. The human data were fit to an amyloid pathway model that provided insight into the Aβ pools affected by BACE1 inhibition and guided the choice of doses for subsequent clinical trials.
Despite continuing debate about the amyloid β-protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer’s disease (AD). Confirmation that presenilin is the catalytic site of γ-secretase has provided a linchpin: all dominant mutations causing early-onsetADoccur either in the substrate (amyloid precursor protein,APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild-typeAPPgene in Down’s syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical ofAD Apolipoprotein E4, which predisposes toADin > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated fromADpatients' brains can decrease synapse number, inhibit long-term potentiation, and enhance long-term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau atAD-relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing humanAPPwith human tau transgenic mice enhances tau-positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid-PETpositivity precede otherADmanifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline inpost hocanalyses of mildADsubjects. Although many factors contribute toADpathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.
The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about two-thirds of which are due to Alzheimer’s disease. The age-specific prevalence of Alzheimer’s disease nearly doubles every 5 years after age 65, leading to a prevalence of greater than 25% in those over the age of 90 (ref. 3). Here, to search for low-frequency variants in the amyloid-β precursor protein (APP) gene with a significant effect on the risk of Alzheimer’s disease, we studied coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. We found a coding mutation (A673T) in the APP gene that protects against Alzheimer’s disease and cognitive decline in the elderly without Alzheimer’s disease. This substitution is adjacent to the aspartyl protease β-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer’s disease provides proof of principle for the hypothesis that reducing the β-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer’s disease, the two may be mediated through the same or similar mechanisms.
BACE1 initiates the generation of the β-amyloid peptide, which likely causes Alzheimer’s disease (AD) when accumulated abnormally. BACE1 inhibitory drugs are currently being developed to treat AD patients. To mimic BACE1 inhibition in adults, we generated BACE1 conditional knockout (BACE1fl/fl) mice and bred BACE1fl/flmice with ubiquitin-CreERmice to induce deletion of BACE1 after passing early developmental stages. Strikingly, sequential and increased deletion of BACE1 in an adult AD mouse model (5xFAD) was capable of completely reversing amyloid deposition. This reversal in amyloid deposition also resulted in significant improvement in gliosis and neuritic dystrophy. Moreover, synaptic functions, as determined by long-term potentiation and contextual fear conditioning experiments, were significantly improved, correlating with the reversal of amyloid plaques. Our results demonstrate that sustained and increasing BACE1 inhibition in adults can reverse amyloid deposition in an AD mouse model, and this observation will help to provide guidance for the proper use of BACE1 inhibitors in human patients.