Apolipoprotein epsilon 4 Modulates Phenotype of Butyrylcholinesterase in CSF of Patients with Alzheimer's Disease

Division of Alzheimer Neurobiology Center, Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Stockholm, Sweden.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 01/2012; 28(2):443-58. DOI: 10.3233/JAD-2011-111088
Source: PubMed


Butyrylcholinesterase K (BCHE-K) is associated with increased risk of developing Alzheimer's disease (AD) in apolipoprotein ε (APOE4) carriers, while among APOE4 non-carriers BCHE-K appears to be protective. Nonetheless, pure pharmacogenetic reports have provided conflicting results. To provide insights about these controversies, we combined BCHE-K pharmacogenetic observations in AD patients (n = 179) with proteomic and enzymatic analysis of plasma, cerebrospinal fluid (CSF), or both samples. We found that BCHE-K genotype was overrepresented among the AD patients (χ(2) = 14.21, p < 0.0001). Plasma BuChE activity was gene dose-dependently 20-50% less among K-carriers (p < 0.001). CSF BuChE activity did not show such robust K-gene dosage-dependency, because K homozygotes (n = 9) had 30-40% less activity compared to both non-carriers (n = 78, p < 0.01) and heterozygotes (n = 42, p < 0.09). CSF ApoE protein expression was also altered by presence of K-allele (p < 0.001, n = 129). Mutually, APOE4 altered phenotypic display of BuChE variants in CSF (p < 0.01, n = 129). In absence of APOE4, CSF BuChE activity was essentially indistinguishable among K-carriers (n = 16) and non-carriers (n = 17, p < 0.8) although the K-carriers had 24-39% less circulating BuChE protein. In contrast in presence of APOE4, the K-carriers (n = 35) had K allele dose-dependently a BuChE phenotype with 14-46% reduced activity compared to K non-carriers (p < 0.001, n = 59), despite an essentially identical BChE concentration in CSF (1 ± 4%, p < 0.8). Pattern of the patients' cognitive performance in MMSE closely resembled the APOE4-derived phenotypic display of BuChE variants. APOE4-dependent outcome of BCHE-K genotype as AD risk factor arises through a differential phenotypic modulation of BuChE. Future pharmacogenetic studies should include assessment of the subjects' true phenotypic display of BuChE.

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    • "The hypothesis that these findings suggest is an inverse U-shaped dynamic profile for the adjustment and maintenance of the appropriate functional status of glial cells in the continuum of AD. Males|BCHE K+ |APOE ␧4+ |<75 y may be at the extreme hypofunctioning end of the inverse-U curve and are most ideally treated with low dose donepezil (Table 1) [15], while Males|BCHE wt/wt may generally be at the top of the inverted-U, representing those with the most dynamic BuChE activity and appropriate glial responses to maintain homeostasis. Females|BCHE wt/wt may be pushed down the overactive downward slope of the inverted-U and are most ideally treated with rivastigmine. "
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    ABSTRACT: Cholinesterase enzymes metabolize acetylcholine (ACh). Inhibition of acetylcholinesterase (AChE) in damaged but functional cholinergic synapses in the brains of dementia patients increases intrasynaptic ACh. This enhances cholinergic neurotransmission and improves cognition. There is a window of opportunity for this symptomatic treatment effect that opens and closes during the course of dementia depending on when significant synaptic damage occurs. Cholinesterases also metabolize extrasynaptic ACh with butyrylcholinesterase (BuChE) apparently playing the major dynamic role in extracellular ACh homeostasis. Extracellular ACh plays a key regulatory role in controlling the reactivity and functional states of non-excitable cells, such as neuroglia. Current inhibitors of cholinesterases (ChEIs) have similar effects on intrasynaptic ACh, but differ markedly in abilities to upregulate extracellular AChE, inhibit BuChE, and influence the fibrilization of amyloid-β peptides. Importantly, ChEIs can have detrimental disease modifying effects in particular individuals characterized by age, gender, and genotype. In contrast, preliminary evidence suggests that the right dose of the right ChEI in the right patient might significantly slow the progression of neurodegenerative processes. For a particular patient, understanding the condition of cholinergic synapses and the reactivity and functional status of neuroglia could allow administration of appropriate ChEI therapy for symptomatic and disease modifying benefits.
    Journal of Alzheimer's disease: JAD 11/2014; 44(4). DOI:10.3233/JAD-142268 · 4.15 Impact Factor
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    • "However, the distribution pattern and observations in acetylcholinesterase (AChE) knockout mice point at the involvement of BuChE in neural function such as coregulation of cholinergic neurotransmission (Darvesh et al., 2003; Mesulam et al., 2002). A substantial number of genetic variants of BCHE have been identified (Darreh-Shori et al., 2012; Darvesh et al., 2003). The BCHE-K variant is the most common functional point mutation of Contents lists available at SciVerse ScienceDirect "
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    ABSTRACT: Butyrylcholinesterase (BuChE) activity is associated with activated astrocytes in Alzheimer's disease brain. The BuChE-K variant exhibits 30%-60% reduced acetylcholine (ACh) hydrolyzing capacity. Considering the increasing evidence of an immune-regulatory role of ACh, we investigated if genetic heterogeneity in BuChE affects cerebrospinal fluid (CSF) biomarkers of inflammation and cholinoceptive glial function. Alzheimer's disease patients (n = 179) were BCHE-K-genotyped. Proteomic and enzymatic analyses were performed on CSF and/or plasma. BuChE genotype was linked with differential CSF levels of glial fibrillary acidic protein, S100B, interleukin-1β, and tumor necrosis factor (TNF)-α. BCHE-K noncarriers displayed 100%-150% higher glial fibrillary acidic protein and 64%-110% higher S100B than BCHE-K carriers, who, in contrast, had 40%-80% higher interleukin-1β and 21%-27% higher TNF-α compared with noncarriers. A high level of CSF BuChE enzymatic phenotype also significantly correlated with higher CSF levels of astroglial markers and several factors of the innate complement system, but lower levels of proinflammatory cytokines. These individuals also displayed beneficial paraclinical and clinical findings, such as high cerebral glucose utilization, low β-amyloid load, and less severe progression of clinical symptoms. In vitro analysis on human astrocytes confirmed the involvement of a regulated BuChE status in the astroglial responses to TNF-α and ACh. Histochemical analysis in a rat model of nerve injury-induced neuroinflammation, showed focal assembly of astroglial cells in proximity of BuChE-immunolabeled sites. In conclusion, these results suggest that BuChE enzymatic activity plays an important role in regulating intrinsic inflammation and activity of cholinoceptive glial cells and that this might be of clinical relevance. The dissociation between astroglial markers and inflammatory cytokines indicates that a proper activation and maintenance of astroglial function is a beneficial response, rather than a disease-driving mechanism. Further studies are needed to explore the therapeutic potential of manipulating BuChE activity or astroglial functional status.
    Neurobiology of aging 06/2013; 34(11). DOI:10.1016/j.neurobiolaging.2013.04.027 · 5.01 Impact Factor
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    • "Whereas carriers of BChE-K and ApoE4 stand an increased risk of Alzheimer's disease, those who do not carry APOE4 appear to be protected, in those with BCHE-K. The interrelationship was hypothesized to arise through a differential phenotypic modulation of BChE by ApoE4, which forms an interesting avenue for future studies [19]. High ApoE was associated with reduced amounts of BChE as well as differentially related to levels of cytokine Il-1B, a proinflammatory cytokine [20]. "
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    ABSTRACT: Butyrylcholinesterase (BChE) is an enzyme which has been shown to be involved in the patho-genesis, treatment and prognosis of Alzheimer's disease. In its current form, however, evidence is equivocal with all of the associations. Variant forms of the protein exist, where the enzymatic function is lost to varying degrees. We performed in silico evaluation of these variants. Bioinfor-matics and molecular modeling, based on data from ESTHER database and Protein Data Bank (RCSB), were used for in silico predictions of the structures of the silent variants that involve a single amino acid change. Variants with loss of enzyme activity were evaluated for structural changes near the active site and the thermody-namic stability of the variants was estimated. The results indicated that the loss of activity of the variants can, in most cases, be attributed to structural changes in the active site or to lower thermodynamic stability. Our results showed that the loss of enzyme activity may be due to changes in the active site, oligomerization or loss of structural stability. Individuals with loss of function mutation of BChE can be studied and followed up for their proneness or resistance to cognitive decline with aging.
    Advances in Alzheimer's Disease 01/2012; 1(01-1):1-11. DOI:10.4236/aad.2012.11001
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