Alkaline Phosphatase Is Increased in both Brain and Plasma in Alzheimer’s Disease

Vardy, Emma; Kellett, Katherine A. B.; Cocklin, Sarah L.; Hooper, Nigel M.

doi:10.1159/000329722

Cited by 79 publications

(64 citation statements)

References 54 publications

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“…In addition, this region also harbors GWAS associations with traits ranging from TNFα response in patients with rheumatoid arthritis (45) to hematologic traits (46). While the physiological function of ALPLs are unknown, and no direct correlations have been made between ALPL variants and cognitive function, tissue non-specific ALPL is increased in Alzheimer’s disease patients (47). Furthermore, Alzheimer’s disease patients have an increased risk of suffering a stroke (48).…”

Section: Discussionmentioning

confidence: 99%

Genetic Associations with Plasma B12, B6, and Folate Levels in an Ischemic Stroke Population from the Vitamin Intervention for Stroke Prevention (VISP) Trial

Keene

Chen

et al. 2014

Front. Public Health

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Background: B vitamins play an important role in homocysteine metabolism, with vitamin deficiencies resulting in increased levels of homocysteine and increased risk for stroke. We performed a genome-wide association study (GWAS) in 2,100 stroke patients from the Vitamin Intervention for Stroke Prevention (VISP) trial, a clinical trial designed to determine whether the daily intake of high-dose folic acid, vitamins B6, and B12 reduce recurrent cerebral infarction.Methods: Extensive quality control (QC) measures resulted in a total of 737,081 SNPs for analysis. Genome-wide association analyses for baseline quantitative measures of folate, Vitamins B12, and B6 were completed using linear regression approaches, implemented in PLINK.Results: Six associations met or exceeded genome-wide significance (P ≤ 5 × 10−08). For baseline Vitamin B12, the strongest association was observed with a non-synonymous SNP (nsSNP) located in the CUBN gene (P = 1.76 × 10−13). Two additional CUBN intronic SNPs demonstrated strong associations with B12 (P = 2.92 × 10−10 and 4.11 × 10−10), while a second nsSNP, located in the TCN1 gene, also reached genome-wide significance (P = 5.14 × 10−11). For baseline measures of Vitamin B6, we identified genome-wide significant associations for SNPs at the ALPL locus (rs1697421; P = 7.06 × 10−10 and rs1780316; P = 2.25 × 10−08). In addition to the six genome-wide significant associations, nine SNPs (two for Vitamin B6, six for Vitamin B12, and one for folate measures) provided suggestive evidence for association (P ≤ 10−07).Conclusion: Our GWAS study has identified six genome-wide significant associations, nine suggestive associations, and successfully replicated 5 of 16 SNPs previously reported to be associated with measures of B vitamins. The six genome-wide significant associations are located in gene regions that have shown previous associations with measures of B vitamins; however, four of the nine suggestive associations represent novel finding and warrant further investigation in additional populations.

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Section: Discussionmentioning

confidence: 99%

Genetic Associations with Plasma B12, B6, and Folate Levels in an Ischemic Stroke Population from the Vitamin Intervention for Stroke Prevention (VISP) Trial

Keene

Chen

et al. 2014

Front. Public Health

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“…ALP is a sensitive marker of liver function and levels are often elevated in obese individuals (Golik et al, 1991). This is concerning, as higher ALP concentrations are seen in Alzheimer's disease patients and correlated with the neurotoxic effects of tau protein (Vardy et al, 2012; Diaz-Hernandez et al, 2010). Fortunately, ALP concentrations have been shown to improve following bariatric surgery (Toolabi et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

The effects of cystatin C and alkaline phosphatase changes on cognitive function 12-months after bariatric surgery

Alosco

Spitznagel

Strain

et al. 2014

Journal of the Neurological Sciences

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Background The mechanisms for improved cognitive function post-bariatric surgery are not well understood. Markers of kidney and liver function (i.e., cystatin C and alkaline phosphatase (ALP)) are elevated in obese individuals and associated with poor neurocognitive outcomes in other samples. Bariatric surgery can improve cystatin C and ALP levels, but no study has examined whether such changes correspond to post-operative cognitive benefits. Methods 78 bariatric surgery patients completed a computerized cognitive test battery prior to and 12-months after surgery. All participants underwent an eight-hour fasting blood draw to quantify cystatin C and ALP concentrations. Results Cognitive function improved after surgery. Cystatin C levels decreased at the 12-month follow-up; however, no changes were found in ALP concentrations. At baseline, higher cystatin C levels predicted worse attention/executive function, but no such effects emerged for ALP. Regression analyses controlling for possible medical and demographic confounds and baseline factors revealed that decreased ALP levels following surgery predicted better attention/executive function and memory abilities. Post-surgery changes in cystatin C did not correspond to cognitive improvements. Conclusions Decreased ALP levels predicted better cognition following bariatric surgery, suggesting improved liver function as a possible mechanism of post-operative cognitive benefits. Future studies with neuroimaging and longer follow-up periods are needed to determine whether bariatric surgery can decrease risk for adverse brain changes and dementia in severely obese persons via improved metabolic function.

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“…Although ecto-nucleotidases, and TNAP in particular, have been studied in Alzheimer disease [31,49], no data were available on human ecto-nucleotidase expression in mental disorders such as SZ. By analyzing brain membranes, we have shown that NTPDase activity (both ATPase and ADPase) is significantly reduced in the putamen of SZ patients when compared with control samples.…”

Section: Discussionmentioning

confidence: 99%

Reduced striatal ecto-nucleotidase activity in schizophrenia patients supports the “adenosine hypothesis”

Aliagas

Villar-Menéndez

Sévigny

et al. 2013

Purinergic Signalling

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Schizophrenia (SZ) is a major chronic neuropsychiatric disorder characterized by a hyperdopaminergic state. The hypoadenosinergic hypothesis proposes that reduced extracellular adenosine levels contribute to dopamine D 2 receptor hyperactivity. ATP, through the action of ecto-nucleotidases, constitutes a main source of extracellular adenosine. In the present study, we examined the activity of ecto-nucleotidases (NTPDases, ecto-5′-nucleotidase, and alkaline phosphatase) in the postmortem putamen of SZ patients (n=13) compared with aged-matched controls (n=10). We firstly demonstrated, by means of artificial postmortem delay experiments, that ectonucleotidase activity in human brains was stable up to 24 h, indicating the reliability of this tissue for these enzyme determinations. Remarkably, NTPDase-attributable activity (both ATPase and ADPase) was found to be reduced in SZ patients, while ecto-5′-nucleotidase and alkaline phosphatase activity remained unchanged. In the present study, we also describe the localization of these ecto-enzymes in human putamen control samples, showing differential expression in blood vessels, neurons, and glial cells. In conclusion, reduced striatal NTPDase activity may contribute to the pathophysiology of SZ, and it represents a potential mechanism of adenosine signalling impairment in this illness.

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Alkaline Phosphatase Is Increased in both Brain and Plasma in Alzheimer’s Disease

Cited by 79 publications

References 54 publications

Genetic Associations with Plasma B12, B6, and Folate Levels in an Ischemic Stroke Population from the Vitamin Intervention for Stroke Prevention (VISP) Trial

Genetic Associations with Plasma B12, B6, and Folate Levels in an Ischemic Stroke Population from the Vitamin Intervention for Stroke Prevention (VISP) Trial

The effects of cystatin C and alkaline phosphatase changes on cognitive function 12-months after bariatric surgery

Reduced striatal ecto-nucleotidase activity in schizophrenia patients supports the “adenosine hypothesis”

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