Differential processing of amyloid precursor protein in brain and in peripheral blood leukocytes

Delvaux, Elaine; Bentley, Karen L. de Mesy; Stubbs, Victoria; Sabbagh, Marwan N.; Coleman, Paul D.

doi:10.1016/j.neurobiolaging.2012.12.004

Cited by 16 publications

(10 citation statements)

References 40 publications

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“…Concentrations of Aβ in cerebrospinal fluid (CSF) are at least 5-15 times higher than those in plasma 7,8 . One possible interpretation is that APP processing in peripheral cells probably occurs via α-cleavage (rather than the β-cleavage used in neurons) 9,10 , resulting in decreased peripheral production of Aβ. Another explanation for the lower Aβ levels in the periphery is that the periphery contains abundant Aβ-binding proteins (lipoproteins and albumin) 11 and Aβ-binding cells, such as erythrocytes 12 , which all contribute to Aβ transportation and clearance.…”

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confidence: 99%

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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The global burden of Alzheimer disease (AD), already the most common type of dementia, is expected to increase still further owing to population ageing. AD not only causes severe distress for patients and caregivers, but also results in a large economic burden on society. Current major challenges in AD include the lack of reliable biomarkers for its early diagnosis, as well as the lack of effective preventive strategies and treatments 1,2 . Thus, increased understanding of the molecular patho genesis of AD could lead to the development of improved diagnostic and therapeutic strategies.AD is conventionally regarded as a CNS disorder. However, increasing experimental, epidemiological and clinical evidence has suggested that manifestations of AD extend beyond the brain. These systemic alterations might not be simply secondary effects of the cerebral degeneration seen in AD, but could reflect under lying processes linked to progression of the disease. AD pathogenesis is complex, involving abnormal amyloid-β (Aβ) metabolism, tau hyperphosphorylation, oxidative stress, reactive glial and microglial changes, and other pathological events. Given that Aβ is a major hallmark of AD and a fertile area of research in this disease, this Review focuses on the systemic role of Aβ in AD. We discuss the communication between peripheral and central pools of Aβ, and describe interactions between systemic abnormalities and AD pathogenesis in the brain. We review emerging findings of associations between systemic abnormalities and Aβ metabolism, and describe how these associations might interact with or reflect on the central pathways of Aβ production and clearance. On the basis of these findings, we suggest that interactions between the brain and the periphery might have a crucial role in the development and progression of AD. Aβ biogenesis and catabolismA steady accrual of data from laboratories and clinics is providing increasing support for the concept that an imbalance between the production and clearance of Aβ is a very early (and often initiating) factor in AD 3 . Normal metabolism of Aβ and maintenance of the homeostatic balance between Aβ production and clearance is, therefore, essential to maintain brain health. In fact, physiological metabolism of Aβ occurs not only in the brain but also in the periphery, and communication between these regions is possible (FIG. 1). Central and peripheral production of AβAβ is derived from the proteolytic cleavage of amyloid precursor protein (APP), which is expressed not only in brain cells, including neurons, astrocytes and microglia, but also in peripheral organs and tissues, such as the Abstract | Alzheimer disease (AD) is the most common type of dementia, and is currently incurable; existing treatments for AD produce only a modest amelioration of symptoms. Research into this disease has conventionally focused on the CNS. However, several peripheral and systemic abnormalities are now understood to be linked to AD, and our understanding of how these alterations contribute to AD is becom...

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A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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“…Amyloid precursor protein (APP) is a type 1 transmembrane glycoprotein that, in AD, is pathologically cleaved to give rise to Aβ peptides of varying length [ 13 ]. We assessed amounts of APP holoprotein in postmortem cortex by probing blots with an antibody specific for C-terminal APP (6E10), which yielded two main bands at 106 and 113 kDa and a faint band at 130 kDa in late-stage AD brain, together characteristic of the three major APP isoforms found in human brain [ 14 , 54 ], Fig. 2a ).…”

Section: Resultsmentioning

confidence: 99%

Upregulation of calpain activity precedes tau phosphorylation and loss of synaptic proteins in Alzheimer’s disease brain

Kurbatskaya

Phillips

Croft

et al. 2016

acta neuropathol commun

113

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Alterations in calcium homeostasis are widely reported to contribute to synaptic degeneration and neuronal loss in Alzheimer’s disease. Elevated cytosolic calcium concentrations lead to activation of the calcium-sensitive cysteine protease, calpain, which has a number of substrates known to be abnormally regulated in disease. Analysis of human brain has shown that calpain activity is elevated in AD compared to controls, and that calpain-mediated proteolysis regulates the activity of important disease-associated proteins including the tau kinases cyclin-dependent kinase 5 and glycogen kinase synthase-3. Here, we sought to investigate the likely temporal association between these changes during the development of sporadic AD using Braak staged post-mortem brain. Quantification of protein amounts in these tissues showed increased activity of calpain-1 from Braak stage III onwards in comparison to controls, extending previous findings that calpain-1 is upregulated at end-stage disease, and suggesting that activation of calcium-sensitive signalling pathways are sustained from early stages of disease development. Increases in calpain-1 activity were associated with elevated activity of the endogenous calpain inhibitor, calpastatin, itself a known calpain substrate. Activation of the tau kinases, glycogen-kinase synthase-3 and cyclin-dependent kinase 5 were also found to occur in Braak stage II-III brain, and these preceded global elevations in tau phosphorylation and the loss of post-synaptic markers. In addition, we identified transient increases in total amyloid precursor protein and pre-synaptic markers in Braak stage II-III brain, that were lost by end stage Alzheimer's disease, that may be indicative of endogenous compensatory responses to the initial stages of neurodegeneration. These findings provide insight into the molecular events that underpin the progression of Alzheimer's disease, and further highlight the rationale for investigating novel treatment strategies that are based on preventing abnormal calcium homeostasis or blocking increases in the activity of calpain or important calpain substrates.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0299-2) contains supplementary material, which is available to authorized users.

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“…In particular, Psen1 mRNA expression levels are similar in the brain and in leukocytes, although different patterns of protein expression were detected in these two tissues, possibly contributing to different post-translational processing of amyloid precursor protein (APP) in the brain and in blood [13]. Therefore, an investigation of the mechanism regulating the control of gene expression might reveal similarities between the brain and peripheral tissues.…”

Section: Introductionmentioning

confidence: 99%

Peripheral leukocyte expression of the potential biomarker proteins Bdnf, Sirt1, and Psen1 is not regulated by promoter methylation in Alzheimer's disease patients

Carboni

Lattanzio

Candeletti

et al. 2015

Neuroscience Letters

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Differential processing of amyloid precursor protein in brain and in peripheral blood leukocytes

Cited by 16 publications

References 40 publications

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

Upregulation of calpain activity precedes tau phosphorylation and loss of synaptic proteins in Alzheimer’s disease brain

Peripheral leukocyte expression of the potential biomarker proteins Bdnf, Sirt1, and Psen1 is not regulated by promoter methylation in Alzheimer's disease patients

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