Selective acetyl- and butyrylcholinesterase inhibitors reduce amyloid-β ex vivo activation of peripheral chemo-cytokines from Alzheimer's disease subjects: Exploring the cholinergic anti-inflammatory pathway

Marcella Reale, Marta Di Nicola, Lucia Velluto, Chiara D'Angelo, Erica Costantini, Debomoy Lahiri, Mohammad A. Kamal, Qian sheng Yu, Nigel H. Greig

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Increasing evidence suggests that elevated production and/or reduced clearance of amyloid-β peptide (Aβ) drives the early pathogenesis of Alzheimer's disease (AD). Aβsoluble oligomers trigger a neurotoxic cascade that leads to neuronal dysfunction, neurodegeneration and, ultimately, clinical dementia. Inflammation, both within brain and systemically, together with a deficiency in the neurotransmitter acetylcholine (ACh) that underpinned the development of anticholinesterases for AD symptomatic treatment, are invariable hallmarks of the disease. The inter-relation between Aβ, inflammation and cholinergic signaling is complex, with each feeding back onto the others to drive disease progression. To elucidate these interactions plasma samples and peripheral blood mononuclear cells (PBMCs) were evaluated from healthy controls (HC) and AD patients. Plasma levels of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and Aβwere significantly elevated in AD vs.HC subjects, and ACh showed a trend towards reduced levels. Aβchallenge of PBMCs induced a greater release of inflammatory cytokines interleukin-1β(IL-1β), monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-α) from AD vs. HC subjects, with IL-10 being similarly affected. THP-1 monocytic cells, a cell culture counterpart of PBMCs and brain microglial cells, responded similarly to Aβas well as to phytohaemagglutinin (PHA) challenge, to allow preliminary analysis of the cellular and molecular pathways underpinning Aβ-induced changes in cytokine expression. As amyloid-βprecursor protein expression, and hence Aβ, has been reported regulated by particular cytokines and anticholinesterases, the latter were evaluated on Aβ- and PHA-induced chemocytokine expression. Co-incubation with selective AChE/BuChE inhibitors, (-)-phenserine (AChE) and (-)-cymserine analogues (BuChE), mitigated the rise in cytokine levels and suggest that augmentation of the cholinergic anti-inflammatory pathway may prove valuable in AD.

Original languageEnglish
Pages (from-to)608-622
Number of pages15
JournalCurrent Alzheimer Research
Volume11
Issue number6
DOIs
StatePublished - 2014

Fingerprint

Butyrylcholinesterase
Cholinesterase Inhibitors
Amyloid
Cholinergic Agents
Alzheimer Disease
Anti-Inflammatory Agents
Cytokines
Blood Cells
Phytohemagglutinins
Acetylcholinesterase
Acetylcholine
Healthy Volunteers
Inflammation
Amyloid beta-Protein Precursor
Chemokine CCL2
Brain
Interleukin-1
Interleukin-10
Neurotransmitter Agents
Dementia

Keywords

  • Acetylcholinesterase (AChE)
  • Alzheimer's disease
  • Amyloid-β peptide (Aβ)
  • Butyrylcholinesterase (BuChE)
  • Cholinesterase inhibitors
  • Cytokines
  • IL-10
  • IL-1β
  • IL-6
  • Inflammation
  • MCP-1
  • Phenserine, cymserine, bisnorcymserine, phytohaemagglutinin (PHA) THP-1 cells, peripheral blood mononuclear cells (PBMCs)
  • TNF-α

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Medicine(all)

Cite this

Selective acetyl- and butyrylcholinesterase inhibitors reduce amyloid-β ex vivo activation of peripheral chemo-cytokines from Alzheimer's disease subjects : Exploring the cholinergic anti-inflammatory pathway. / Reale, Marcella; Di Nicola, Marta; Velluto, Lucia; D'Angelo, Chiara; Costantini, Erica; Lahiri, Debomoy; Kamal, Mohammad A.; Yu, Qian sheng; Greig, Nigel H.

In: Current Alzheimer Research, Vol. 11, No. 6, 2014, p. 608-622.

Research output: Contribution to journalArticle

Reale, Marcella ; Di Nicola, Marta ; Velluto, Lucia ; D'Angelo, Chiara ; Costantini, Erica ; Lahiri, Debomoy ; Kamal, Mohammad A. ; Yu, Qian sheng ; Greig, Nigel H. / Selective acetyl- and butyrylcholinesterase inhibitors reduce amyloid-β ex vivo activation of peripheral chemo-cytokines from Alzheimer's disease subjects : Exploring the cholinergic anti-inflammatory pathway. In: Current Alzheimer Research. 2014 ; Vol. 11, No. 6. pp. 608-622.
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AU - Di Nicola, Marta

AU - Velluto, Lucia

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AU - Kamal, Mohammad A.

AU - Yu, Qian sheng

AU - Greig, Nigel H.

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