Alzheimer’s disease (AD) is the most prevalent form of dementia worldwide. It is characterized by synaptic deficits, excessive β-amyloid (Aβ) accumulation, and hyperphosphorylation of intraneuronal tau protein in brain. However, the mechanisms underlying AD pathology is unclear, and no effective treatment has been developed. Reduced α-melanocyte-stimulating hormone (α-MSH) in cerebrospinal fluid is associated with AD pathogenesis. Alpha-MSH is the endogenous agonist of melanocortin-4 receptor (MC4R) that derived from post-translational cleavage of its propeptide, proopiomelanocortin (POMC). Previously, our group has identified that MC4R signaling is important for the maintenance and modulation of synaptic plasticity. However, the mechanism underlying the functions of POMC/MC4R s...[ Read more ]

Alzheimer’s disease (AD) is the most prevalent form of dementia worldwide. It is characterized by synaptic deficits, excessive β-amyloid (Aβ) accumulation, and hyperphosphorylation of intraneuronal tau protein in brain. However, the mechanisms underlying AD pathology is unclear, and no effective treatment has been developed. Reduced α-melanocyte-stimulating hormone (α-MSH) in cerebrospinal fluid is associated with AD pathogenesis. Alpha-MSH is the endogenous agonist of melanocortin-4 receptor (MC4R) that derived from post-translational cleavage of its propeptide, proopiomelanocortin (POMC). Previously, our group has identified that MC4R signaling is important for the maintenance and modulation of synaptic plasticity. However, the mechanism underlying the functions of POMC/MC4R signaling in AD pathogenesis need to be investigated.

POMC-MC4R signaling is well known for its function in governing food intake and energy homeostasis in hypothalamus, where POMC and MC4R are expressed in different subregions and work through neuronal circuit. Therefore, the expression patterns of POMC and MC4R in hippocampus are investigated in the current study. The results show that they are expressed with different levels among hippocampal subregions. POMC expressing cells are mainly pyramidal neurons cluster in the cornu ammonis (CA) 2/3 region, and sending their axonal projections to the CA1 region. Meanwhile, MC4R is highly expressed in CA1 pyramidal cell layers, indicating that POMC/MC4R signaling may be important for functions in the CA3–CA1 microcircuit, i.e., the Schaffer collateral (SC)-CA1 pathway. Interestingly, the number of POMC-expressing neurons and α-MSH level in the hippocampus changes during aging, peaking at 9 months in wild type mice. However, transgenic APP/PS1 mice do not exhibit increased α-MSH level at the same age, possibly because of the vulnerability of POMC neurons to Aβ; accordingly, acute Aβ treatment decreases POMC transcription level in hippocampal slices.

Further studies show that hippocampal POMC/MC4R signaling is implicated in learning and memory under AD pathological conditions. Long-term potentiation (LTP) in the SC–CA1 pathway is a cellular mechanism of learning and memory. The current study reveals that LTP is impaired in APP/PS1 mice and is exacerbated by the downregulation of MC4R signaling. Interestingly, up-regulation of MC4R signaling ameliorates the synaptic plasticity impairment caused by Aβ and rescues the LTP deficit in APP/PS1 mice. Notably, the effect of MC4R signaling on LTP is mediated through the downstream effector, Gαs. Importantly, MC4R activation rescues Aβ-induced synaptic dysfunction via a Gs/cyclic AMP (cAMP)/PKA/cAMP-response element binding protein (CREB)-dependent mechanism.

POMC/MC4R also play a role in Aβ accumulation. Aβ is produced by cleavage of full length amyloid precursor protein (flAPP) by β- and γ-secretases consequently. The current study reveals that MC4R activation decreases Aβ accumulation in the brain, especially the hippocampus where MC4R is highly expressed, while knockdown MC4R abolished this effect. Similarly, overexpression of POMC in CA3 regions could also reduce Aβ accumulation in the hippocampus. In addition, the reduction of Aβ accumulation is higher in hippocampal laminas that involve CA3 axonal processes than other laminas. Interestingly, chronic D-Tyr MTII (an MC4R agonist) treatment not only reduces Aβ level, but also reduces flAPP phosphorylation at Thr668 (pT668APP) in the hippocampus. On the other hand, chronic HS024 (an MC4R antagonist) treatment or direct activation of Gαs does not change Aβ accumulation. Moreover, D-Tyr MTII reduces β-CTF, sAPPβ and flAPP in the hippocampus under both acute and chronic conditions. Meanwhile, some endosome-lysosome markers in protein degradation pathway are changed by D-Tyr MTII. There results collectively indicate that POMC/MC4R signaling activation reduces Aβ accumulation through Gs/cAMP/PKA independent manner.

In summary, POMC/MC4R signaling is impaired under AD pathological conditions. Activation of POMC/MC4R rescues synaptic dysfunction in AD and reduces Aβ accumulation. Therefore, POMC/MC4R may become a new target for drug development in AD.