Opioid system and Alzheimer's disease.

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.