Prospective Study of Risk Factors for Alzheimer’s Disease: Results at 7.5 Years

Zubenko, George S.; E, Winwood; Jacobs, Barbara; Teply, Ivana; Stiffler, J. Scott; Hughes, Hugh B.; Huff, F. Jacob; Sunderland, Trey; Martínez, A. Julio

doi:10.1176/ajp.156.1.50

Cited by 23 publications

(6 citation statements)

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“…Previous studies during the 1980s and 90s reported a possible relationship between increased platelet membrane fluidity, which increases when membrane cholesterol level is reduced, and AD (reviewed by Swiderek et al 1997), although few developments have been published more recently. Internal membranes have a lower ratio of cholesterol to phospholipid than plasma membranes, and the increased platelet membrane fluidity in AD was attributed to a proliferation in internal membranes, rather than changes in plasma membrane lipid composition (Cohen et al 1987;Piletz et al 1991;Zubenko et al 1999). One study also reported a slight (5%) decrease in platelet membrane cholesterol level in a small group (n = 10) of Alzheimer's patients, but this was not statistically significant (Cohen et al 1987).…”

Section: Discussionmentioning

confidence: 99%

A novel reciprocal and biphasic relationship between membrane cholesterol and β‐secretase activity in SH‐SY5Y cells and in human platelets

Liu

Todd

Coulson

et al. 2008

Journal of Neurochemistry

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Research into the cause of Alzheimer's disease (AD) has identified strong connections to cholesterol. Cholesterol and cholesterol esters can modulate amyloid precursor protein (APP) processing, thus altering production of the Ab peptides that deposit in cortical amyloid plaques. Processing depends on the encounter between APP and cellular secretases, and is thus subject to the influence of cholesterol-dependent factors including protein trafficking, and distribution between membrane subdomains. We have directly investigated endogenous membrane b-secretase activity in the presence of a range of membrane cholesterol levels in SH-SY5Y human neuroblastoma cells and human platelets. Membrane cholesterol significantly influenced membrane b-secretase activity in a biphasic manner, with positive correlations at higher membrane cholesterol levels, and negative correlations at lower membrane cholesterol levels. Platelets from individuals with AD or mild cognitive impairment (n = 172) were significantly more likely to lie within the negative correlation zone than control platelets (n = 171). Pharmacological inhibition of SH-SY5Y b-secretase activity resulted in increased membrane cholesterol levels. Our findings are consistent with the existence of a homeostatic feedback loop between membrane cholesterol level and membrane b-secretase activity, and suggest that this regulatory mechanism is disrupted in platelets from individuals with cognitive impairment. Keywords: Alzheimer's disease, amyloid precursor protein, cognitive impairment, platelet, protease, statin. all studies have supported these findings, reviewed by Rockwood 2006). We have studied APP cleavage at the N-terminus of Ab (bsecretase site), the rate-limiting step for Ab formation. Two 'b-secretase' proteases have been identified: b-site APP cleaving enzymes 1 and 2 (BACE1/memapsin 2/EC 3.4.23.46 and BACE2/memapsin 1/EC 3.4.23.45) (Sinha et al. 1999;Vassar et al. 1999;Farzan et al. 2000). Elevations in brain b-secretase activity have been found in AD (Fukumoto et al. 2002;Holsinger et al. 2002;Li et al. 2004;Stockley et al. 2006;Zhao et al. 2007); and in CSF (Holsinger et al. 2004). However, little is currently known about endogenous regulation of b-secretase activity. Most previous studies have indicated that cellular cholesterol influenced generation of Ab, but crucially, the studies examined APP processing or Ab production rather than secretase activity per se. As APP processing is dependent on APP encountering the appropriate secretases within the cell, it is likely to be sensitive to cholesterol-dependent events, such as protein trafficking and distribution of proteins between membrane subdomains. One study addressed this by using recombinant BACE1 in an artificial membrane system, reporting lipid-mediated effects on proteolytic activity (Kalvodova et al. 2005). We and another group (Grimm et al. 2008) studied a more physiological system by directly investigating endogenous membrane b-secretase activity. We have also simultaneously measured membrane...

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Section: Discussionmentioning

confidence: 99%

A novel reciprocal and biphasic relationship between membrane cholesterol and β‐secretase activity in SH‐SY5Y cells and in human platelets

Liu

Todd

Coulson

et al. 2008

Journal of Neurochemistry

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“…Platelets are frequently used as peripheral markers for neurons because they share some common membrane and receptor properties, providing, thus, an interesting model for the investigation of metabolic abnormalities in AD (Zubenko et al 1999). There is indirect evidence that brain and platelet PLA 2 activity are under similar regulatory control.…”

Section: Cognitive Training Induces Pla 2 Activation In Platelets Of mentioning

confidence: 99%

Phospholipase A2 activation as a therapeutic approach for cognitive enhancement in early-stage Alzheimer disease

2008

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“…As we are currently unable to have brain or CSF samples from these T2DM patients, we are unfortunately not able to identify whether the platelet GSK-3β activation reflects GSK-3β activation in the central nervous system or to provide direct evidence revealing the possible biological relationship between platelet GSK-3β and cognitive impairment. Nonetheless, platelets are frequently used to search for peripheral biomarkers for the nervous system because they share many biochemical similarities, such as accumulation and release of neurotransmitters, responses to variations of calcium concentration, and expression of receptors and enzymes, and therefore, the platelet has served as an important model for the investigation of metabolic abnormalities in AD ( Zubenko et al, 1999 ; Gattaz et al, 2004 ; Forlenza et al, 2011 ). How exactly the platelet GSK-3β activation may reflect brain GSK-3β activation and its biological relations with cognitive impairment deserve further investigation.…”

Section: Discussionmentioning

confidence: 99%

Periphery Biomarkers for Objective Diagnosis of Cognitive Decline in Type 2 Diabetes Patients

Liu

Zhang

et al. 2021

Front. Cell Dev. Biol.

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Introduction: Type 2 diabetes mellitus (T2DM) is an independent risk factor of Alzheimer’s disease (AD), and populations with mild cognitive impairment (MCI) have high incidence to suffer from AD. Therefore, discerning who may be more vulnerable to MCI, among the increasing T2DM populations, is important for early intervention and eventually decreasing the prevalence rate of AD. This study was to explore whether the change of plasma β-amyloid (Aβ) could be a biomarker to distinguish MCI (T2DM-MCI) from non-MCI (T2DM-nMCI) in T2DM patients.Methods: Eight hundred fifty-two T2DM patients collected from five medical centers were assigned randomly to training and validation cohorts. Plasma Aβ, platelet glycogen synthase kinase-3β (GSK-3β), apolipoprotein E (ApoE) genotypes, and olfactory and cognitive functions were measured by ELISA, dot blot, RT-PCR, Connecticut Chemosensory Clinical Research Center (CCCRC) olfactory test based on the diluted butanol, and Minimum Mental State Examination (MMSE) test, respectively, and multivariate logistic regression analyses were applied.Results: Elevation of plasma Aβ1-42/Aβ1-40 is an independent risk factor of MCI in T2DM patients. Although using Aβ1-42/Aβ1-40 alone only reached an AUC of 0.631 for MCI diagnosis, addition of the elevated Aβ1-42/Aβ1-40 to our previous model (i.e., activated platelet GSK-3β, ApoE ε4 genotype, olfactory decline, and aging) significantly increased the discriminating efficiency of T2DM-MCI from T2DM-nMCI, with an AUC of 0.846 (95% CI: 0.794–0.897) to 0.869 (95% CI: 0.822–0.916) in the training cohort and an AUC of 0.848 (95% CI: 0.815–0.882) to 0.867 (95% CI: 0.835–0.899) in the validation cohort, respectively.Conclusion: A combination of the elevated plasma Aβ1-42/Aβ1-40 with activated platelet GSK-3β, ApoE ε4 genotype, olfactory decline, and aging could efficiently diagnose MCI in T2DM patients. Further longitudinal studies may consummate the model for early prediction of AD.

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Prospective Study of Risk Factors for Alzheimer’s Disease: Results at 7.5 Years

Cited by 23 publications

References 81 publications

A novel reciprocal and biphasic relationship between membrane cholesterol and β‐secretase activity in SH‐SY5Y cells and in human platelets

A novel reciprocal and biphasic relationship between membrane cholesterol and β‐secretase activity in SH‐SY5Y cells and in human platelets

Phospholipase A2 activation as a therapeutic approach for cognitive enhancement in early-stage Alzheimer disease

Periphery Biomarkers for Objective Diagnosis of Cognitive Decline in Type 2 Diabetes Patients

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