Protective effects of intracerebroventricular adiponectin against olfactory impairments in an amyloid β1–42 rat model

Abstract

Background Alzheimer’s disease (AD) is characterized by cognitive impairment that eventually develops into dementia. Amyloid-beta (Aβ) accumulation is a widely described hallmark in AD, and has been reported to cause olfactory dysfunction, a condition considered an early marker of the disease associated with injuries in the olfactory bulb (OB), the hippocampus (HIPP) and other odor-related cortexes. Adiponectin (APN) is an adipokine with neuroprotective effects. Studies have demonstrated that APN administration decreases Aβ neurotoxicity and Tau hyperphosphorylation in the HIPP, reducing cognitive impairment. However, there are no studies regarding the neuroprotective effects of APN in the olfactory dysfunction observed in the Aβ rat model. The aim of the present study is to determine whether the intracerebroventricular (i.c.v) administration of APN prevents the early olfactory dysfunction in an i.c.v Amyloid-beta1–42 (Aβ1–42) rat model. Hence, we evaluated olfactory function by using a battery of olfactory tests aimed to assess olfactory memory, discrimination and detection in the Aβ rat model treated with APN. In addition, we determined the number of cells expressing the neuronal nuclei (NeuN), as well as the number of microglial cells by using the ionized calcium-binding adapter molecule 1 (Iba-1) marker in the OB and, CA1, CA3, hilus and dentate gyrus (DG) in the HIPP. Finally, we determined Arginase-1 expression in both nuclei through Western blot. Results We observed that the i.c.v injection of Aβ decreased olfactory function, which was prevented by the i.c.v administration of APN. In accordance with the olfactory impairment observed in i.c.v Aβ-treated rats, we observed a decrease in NeuN expressing cells in the glomerular layer of the OB, which was also prevented with the i.c.v APN. Furthermore, we observed an increase of Iba-1 cells in CA1, and DG in the HIPP of the Aβ rats, which was prevented by the APN treatment. Conclusion The present study describes the olfactory impairment of Aβ treated rats and evidences the protective role that APN plays in the brain, by preventing the olfactory impairment induced by Aβ1–42. These results may lead to APN-based pharmacological therapies aimed to ameliorate AD neurotoxic effects.

Adiponectin and resistin modulate the progression of Alzheimer´s disease in a metabolic syndrome model

“…Consistent with earlier studies, ApN treatment results in a significant reduction of Aβ 1-42 levels, while ApN deficiency accelerates Aβ pathology ( 93 , 100 – 102 , 103 ). Hahm and coworkers proposed that HFD consumption causes metabolic perturbations and ApN deficiencies that suppress ApN receptor-mediated AMP-activated protein kinase (AMPK) phosphorylation.…”

The olfactory bulb: A neuroendocrine spotlight on feeding and metabolism

“…183,184 In a rat model adiponectin prevented olfactory impairment induced by amyloid-beta accumulation, probably due to its described neuroprotective effects. 185 Interestingly, plasma adiponectin concentrations correlate with greater olfactory sensitivity in women, but not men. 186 Further, it has been suggested that adiponectin may modulate insulin signalling in the OB, possibly contributing to olfactory performance.…”

“…In the OB, both receptors (adipoR1 and 2) have been identified in the periglomerular, mitral and granular cell layers 183,184 . In a rat model adiponectin prevented olfactory impairment induced by amyloid‐beta accumulation, probably due to its described neuroprotective effects 185 . Interestingly, plasma adiponectin concentrations correlate with greater olfactory sensitivity in women, but not men 186 .…”

Metabolic Disturbances Induced by Sleep Restriction as Potential Triggers for Alzheimer’s Disease

“…(3) adiponectin receptors are expressed in the central nervous system (CNS; Bloemer et al, 2018); and (4) adiponectin knockout mice perform poorly on the new object recognition test and exhibit LTP deficiency (Bloemer et al, 2019). Further, in a rat model in which olfactory memory impairment and olfactory damage were caused by intracerebroventricular administration of Aβ 41-42 , intracerebroventricular (icv) adiponectin prevented olfactory memory impairments (Guzmán-Ruiz et al, 2021), which are common early symptoms in patients with MCI and AD.…”