A₁ Adenosine Receptors Accumulate in Neurodegenerative Structures in Alzheimer's Disease and Mediate Both Amyloid Precursor Protein Processing and Tau Phosphorylation and Translocation

Abstract

Immunostaining of adenosine receptors in the hippocampus and cerebral cortex from necropsies of Alzheimer's disease (AD) patients shows that there is a change in the pattern of expression and a redistribution of receptors in these brain areas when compared with samples from controls. Adenosine A1 receptor (A1R) immunoreactivity was found in degenerating neurons with neurofibrillary tangles and in dystrophic neurites of senile plaques. A high degree of colocalization for A1R and pA4 amyloid in senile plaques and for A1R and tau in neurons with tau deposition, but without tangles, was seen. Additionally, adenosine A2A receptors, located mainly in striatal neurons in controls, appeared in glial cells in the hippocampus and cerebral cortex of patients. On comparing similar samples from controls and patients, no significant change was evident for metabotropic glutamate receptors. In the human neuroblastoma SH‐SY5Y cell line, agonists for A1R led to a dose‐dependent increase in the production of soluble forms of amyloid precursor protein in a process mediated by PKC. A1R agonist induced p21 Ras activation and ERK1/2 phosphorylation. Furthermore, activation of A1R led to and ERK‐dependent increase of tau phosphorylation and translocation towards the cytoskeleton. These results indicate that adenosine receptors are potential targets for AD.

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

“…This decreased density of A 1 Rs is in general agreement with the development of tolerance in relation to the anti-convulsive effects of A 1 receptor agonists [198,199] that is accompanied by a reduced potency of A 1 R agonists [120]. In other chronic neurodegenerative conditions, such as Alzheimer's disease, the density of A 1 Rs is also reduced ( [206,397,398]; but see [207]). Likewise, several studies showed that short periods of brain ischemia, which also trigger a robust increase in the extracellular levels of adenosine ( [121]; reviewed in [172]), produce a long-lasting decrease in the density of A 1 Rs in several brain regions (e.g., [200Y202]).…”

“…It was observed that convulsive behaviour caused a longterm robust enhancement of the density of cortical A 2A Rs, which contrasted with the decreased density of cortical A 1 Rs [195]. Likewise, in brain sections from patients with Alzheimer's disease, a greater density of A 2A Rs was also observed, which was reported to be confined to microglia processes [207]. This is in agreement with the recently reported increased in the density of A 2A Rs in activated microglia cells [216] and with the ability of cytokines to up-regulate A 2A Rs [217].…”

Adenosine A 1 receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280

“…Adverse effects were, however, limited (30). It has been reported that adenosine receptors are increased in neurons in the degenerating human brain and that administration of an adenosine A 1 receptor agonist induces Aβ production, Tau phosphorylation, and Tau missorting in vitro (31). Down syndrome patients, known to suffer from early-onset AD, have higher levels of adenosine than aged matched controls (32).…”

Adenosine A1 receptor-mediated transactivation of the EGF receptor produces a neuroprotective effect on cortical neurons in vitro

“…A 1 R is often associated with cellular responses to ischemic and metabolic stress. Previous results [34] have shown that A 1 R accumulates in neurodegenerative brain tissues in Alzheimer disease and mediates both amyloid precursor protein processing and Tau phosphorylation and translocation. Therefore, further in-depth study of the transactivation and regulation of EGFR by A 1 R, in particular the neuroprotective and synergistic action of their ligands, would be important for the development of novel therapeutic strategies and drugs effective against neurodegenerative diseases.…”