Proteolytic processing of the Alzheimer's disease amyloid precursor protein in brain and platelets

Evin, Geneviève; Zhu, Aiqin; Holsinger, R. M. Damian; Masters, Colin L.; Li, Qiao‐Xin

doi:10.1002/jnr.10745

Cited by 137 publications

(108 citation statements)

References 63 publications

(77 reference statements)

Supporting

Mentioning

100

Contrasting

Unclassified

Order By: Relevance

“…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.…”

mentioning

confidence: 99%

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

et al. 2017

Self Cite

View full text Add to dashboard Cite

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...

show abstract

mentioning

confidence: 99%

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

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…The inhibitory effect of ATRA on A␤ accumulation is likely attributable to its inhibition of APP processing, because the production of APP-CTFs, the direct precursor of A␤ (Evin et al, 2003), was attenuated by the ATRA treatment. In addition, a previous study has shown that ATRA prevents formation of fibrillar A␤ from fresh A␤ (Ono et al, 2004), suggesting that ATRA is involved in multiple steps of A␤ deposition.…”

Section: Discussionmentioning

confidence: 99%

“…APP is cleaved by BACE1 enzyme at the N-terminal region, producing membrane-bound C-terminal fragments (APP-CTFs) (Evin et al, 2003). APPCTFs are considered potential early markers for the biological diagnosis of AD (Sergeant et al, 2002).…”

Section: Atra Prevents App Processing and Phosphorylation Of Both Appmentioning

confidence: 99%

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

Ding¹,

et al. 2008

View full text Add to dashboard Cite

Recent studies have revealed that disruption of vitamin A signaling observed in Alzheimer's disease (AD) leads to ␤-amyloid (A␤) accumulation and memory deficits in rodents. The aim of the present study was to evaluate the therapeutic effect of all-trans retinoic acid (ATRA), an active metabolite of vitamin A, on the neuropathology and deficits of spatial learning and memory in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic mice, a well established AD mouse model. Here we report a robust decrease in brain A␤ deposition and tau phosphorylation in the blinded study of APP/PS1 transgenic mice treated intraperitoneally for 8 weeks with ATRA (20 mg/kg, three times weekly, initiated when the mice were 5 months old). This was accompanied by a significant decrease in the APP phosphorylation and processing. The activity of cyclin-dependent kinase 5, a major kinase involved in both APP and tau phosphorylation, was markedly downregulated by ATRA treatment. The ATRA-treated APP/PS1 mice showed decreased activation of microglia and astrocytes, attenuated neuronal degeneration, and improved spatial learning and memory compared with the vehicle-treated APP/ PS1 mice. These results support ATRA as an effective therapeutic agent for the prevention and treatment of AD.

show abstract

“…The dams that received the methionine supplement (DSD) showed, after twenty days of treatment, an increase in Hcy concentration of approximately 100% (8.71 µmol/L) compared to the control group (DCT) (4.45 µmol/L) (t (11) =5.59, p<0.001) (Figure 1). …”

Section: Damsmentioning

confidence: 99%

“…Amyloid-beta (Aβ) brain deposits are one of the hallmarks of the neuropathological degeneration observed in AD patients, and Aβ is produced by two sequential proteolytic cleavages of amyloid precursor protein (APP). APP can be processed by α-secretases (PS1 and PS2) and γ-secretases (ADAM10 and TACE) producing non-amyloidogenic peptides, or by α-secretases and β-secretases (BACE) producing the Aβ fragments [11][12][13]. PS1 and BACE are regulated by methylation and decreased folate and vitamin B12 in culture media can cause a decrease in S-adenosylmethionine (SAM), a universal donor of methyl groups, and an increase Aβ concentration [14].…”

Section: Introductionmentioning

confidence: 99%

Hyperhomocysteinemia and Gestational Programming of Genes Involved in Alzheimer’s Disease Pathogenesis

Silva¹

2014

J Nutr Food Sci

View full text Add to dashboard Cite

Sciencesda Silva et al., J Nutr Food Sci 2013, 4:1 http://dx.doi.org/10.4172/2155-9600.1000253 *Corresponding author: Vânia D'Almeida, R. Napoleão de Barros, nº 925, 3º andar, São Paulo-SP, Brazil, CEP: 04024-002, Brazil, Tel: 55-11-21490155; Fax: 55-11-55725092; E-mail: vaniadalmeida@uol.com AbstractMaternal hyperhomocysteinemia (hHcy) induced by a high methionine diet delays brain maturation and leads to impairment of learning performance in the offspring. Because methionine-homocysteine metabolism is related to the regulation of gene expression through one-carbon metabolism, we investigated whether maternal supplementation with methionine affects the expression of Adam10, Bace1, Bace2, Ps1, Ps2, Tace, App, and Tnf-α, genes related to Alzheimer's disease (AD) risk, in the offspring. Thirteen female mice were distributed into the following groups: a) standard diet and b) standard diet supplemented with 1% methionine in water. After birth, the offspring were organized into Control (CT) and Supplemented Diet (SD) groups, and at Postnatal Day (PND) 90, all animals were weighed and then euthanized. The homocysteine (Hcy) concentration in plasma was measured, and the whole brain was weighed and dissected, and the hippocampus used for gene expression analyses. A decrease in total body weight was found in SD group, but no differences in brain weight were observed. The maternal diet did not seem to affect the Hcy concentration of PND 90 offspring. No differences were found in the expression of AD related genes in the hippocampus (p>0.05). In conclusion, hHcy induced by methionine supplementation during pregnancy and lactation did not affect the expression of genes related to AD risk in the offspring.

show abstract

Proteolytic processing of the Alzheimer's disease amyloid precursor protein in brain and platelets

Cited by 137 publications

References 63 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

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

Hyperhomocysteinemia and Gestational Programming of Genes Involved in Alzheimer’s Disease Pathogenesis

Contact Info

Product

Resources

About