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Opioid System and Alzheimer’s Disease

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Abstract

The opioid system may be involved in the pathogenesis of AD, including cognitive impairment, hyperphosphorylated tau, Aβ production, and neuroinflammation. Opioid receptors influence the regulation of neurotransmitters such as acetylcholine, norepinephrine, GABA, glutamate, and serotonin which have been implicated in the pathogenesis of AD. Opioid system has a close relation with Aβ generation since dysfunction of opioid receptors retards the endocytosis and degradation of BACE1 and γ-secretase and upregulates BACE1 and γ-secretase, and subsequently, the production of Aβ. Conversely, activation of opioid receptors increases the endocytosis of BACE1 and γ-secretase and downregulates BACE1 and γ-secretase, limiting the production of Aβ. The dysfunction of opioid system (opioid receptors and opioid peptides) may contribute to hyperphosphorylation of tau and neuroinflammation, and accounts for the degeneration of cholinergic neurons and cognitive impairment. Thus, the opioid system is potentially related to AD pathology and may be a very attractive drug target for novel pharmacotherapies of AD.

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Abbreviations

Aβ:

Beta-amyloid

ACTH:

Adrenocorticotropin hormone

AD:

Alzheimer’s disease

ADAMS:

Aging, Demographics, and Memory Study

APP:

Amyloid precursor protein

BACE:

Beta-site APP-cleaving enzyme

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

CaMKII:

Ca2+/calmodulin-dependent protein kinase II

DOR:

Delta-opioid receptor

DAGO:

Tyr-D-Ala-Gly- (Me) Phe-Gly-ol

DADPE:

D-Ala2, D-Leu5 enkephalin

DSLET:

D-Ser2, Thr6 Leu5 enkephalin

GABA:

Gamma aminobutyric acid

KOR:

Kappa-opioid receptor

LC:

Locus ceruleus

LPH:

α, β, and γ-Lipotropin

LTP:

Long-term potentiation

MDMA:

3,4-Methylenedioxymethamphetamine

MEK:

Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase

MSH:

α- and β-Melanotropin

MOR:

Mu-opioid receptor

NMDA:

N-methyl-d-aspartate

NOP:

Nociceptin receptor

NFT:

Neurofibrillary tangles

OR:

Opioid receptor

OGFr:

Opioid growth factor receptor

ORL1:

Opioid receptor-like receptor

PHF:

Paired helical

PI3K:

Phosphatidilinositol-3 kinase

PNOC:

Prepronociceptin PNS: peripheral nervous system

PET:

Positron Emission Tomography

SPECT:

Single Photon Emission Computed Tomography

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Acknowledgments

This work was supported by the start-up funds from Texas A&M Health Science Center to Dr. Anna Ratka.

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Authors and Affiliations

  1. Department of Neurology, The Lu’an Affiliated Hospital of Anhui Medical University, Lu’an People’s Hospital, Lu’an, 237005, Anhui Province, China

    Zhiyou Cai

  2. Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, MSC 131, 1010 West Avenue B, Kingsville, TX, 78363, USA

    Anna Ratka

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  1. Zhiyou Cai
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Correspondence to Anna Ratka.

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Cai, Z., Ratka, A. Opioid System and Alzheimer’s Disease. Neuromol Med 14, 91–111 (2012). https://doi.org/10.1007/s12017-012-8180-3

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