Adiponectin-mimetic novel nonapeptide rescues aberrant neuronal metabolic-associated memory deficits in Alzheimer’s disease

Abstract

Background Recently, we and other researchers reported that brain metabolic disorders are implicated in Alzheimer’s disease (AD), a progressive, devastating and incurable neurodegenerative disease. Hence, novel therapeutic approaches are urgently needed to explore potential and novel therapeutic targets/agents for the treatment of AD. The neuronal adiponectin receptor 1 (AdipoR1) is an emerging potential target for intervention in metabolic-associated AD. We aimed to validate this hypothesis and explore in-depth the therapeutic effects of an osmotin-derived adiponectin-mimetic novel nonapeptide (Os-pep) on metabolic-associated AD. Methods We used an Os-pep dosage regimen (5 μg/g, i.p., on alternating days for 45 days) for APP/PS1 in amyloid β oligomer-injected, transgenic adiponectin knockout (Adipo−/−) and AdipoR1 knockdown mice. After behavioral studies, brain tissues were subjected to biochemical and immunohistochemical analyses. In separate cohorts of mice, electrophysiolocal and Golgi staining experiments were performed. To validate the in vivo studies, we used human APP Swedish (swe)/Indiana (ind)-overexpressing neuroblastoma SH-SY5Y cells, which were subjected to knockdown of AdipoR1 and APMK with siRNAs, treated with Os-pep and other conditions as per the mechanistic approach, and we proceeded to perform further biochemical analyses. Results Our in vitro and in vivo results show that Os-pep has good safety and neuroprotection profiles and crosses the blood-brain barrier. We found reduced levels of neuronal AdipoR1 in human AD brain tissue. Os-pep stimulates AdipoR1 and its downstream target, AMP-activated protein kinase (AMPK) signaling, in AD and Adipo−/− mice. Mechanistically, in all of the in vivo and in vitro studies, Os-pep rescued aberrant neuronal metabolism by reducing neuronal insulin resistance and activated downstream insulin signaling through regulation of AdipoR1/AMPK signaling to consequently improve the memory functions of the AD and Adipo−/− mice, which was associated with improved synaptic function and long-term potentiation via an AdipoR1-dependent mechanism. Conclusion Our findings show that Os-pep activates AdipoR1/AMPK signaling and regulates neuronal insulin resistance and insulin signaling, which subsequently rescues memory deficits in AD and adiponectin-deficient models. Taken together, the results indicate that Os-pep, as an adiponectin-mimetic novel nonapeptide, is a valuable and promising potential therapeutic candidate to treat aberrant brain metabolism associated with AD and other neurodegenerative diseases.

Adiponectin Modulation by Genotype and Maternal Choline Supplementation in a Mouse Model of Down Syndrome and Alzheimer’s Disease

“…In contrast to APN, no changes in ADIPOR1 or ADIPOR2 mRNA or protein levels were seen due to the genotype in Fr Ctx at~6 MO (Figure 2), which may reflect compensatory mechanisms seen in these mice in early adulthood, or regional/cellular specificity in gene expression changes. Previous work in an AD mouse model found no changes in Adipor1, but decreased Adipor2 levels in Fr Ctx [100,101]. No significant changes in protein levels for either receptor was reported [100], consistent with our findings in the trisomic mouse model.…”

“…Downregulation of APN levels in trisomic mice is commensurate with findings in several human studies in DS [34,50], AD [52,56] and mild cognitive impairment with T2DM [97], where decreased APN concentrations are found. Studies in brain tissue from animal models of neurodegeneration show that APN and APN receptors impact signaling and neuronal function in the brain, including neuronal insulin resistance, synaptic plasticity, excitotoxicity, neurodegeneration and cognitive decline [48,49,96,[98][99][100][101]. While leptin levels are increased in peripheral studies in persons with DS [24], no studies have reported changes in CNS.…”

“…Knockdown of Adipor1 expression resulted in neurodegenerative phenotypes, spatial learning and memory deficits, and insulin signaling dysfunction in the hippocampus [99]. Further, delivery of an APN nonapeptide mimetic which activates APN receptors restores synaptic function in Adipor1 knockdown mice [101]. In human brain tissue, ADIPOR1 displays high expression in the nucleus basalis of Meynert (NBM) of the basal forebrain [93].…”

“…Therefore, loss of APN expression in trisomic mice may be linked to BFCN degeneration and could be a selective alteration found in basal forebrain [98] or in the septohippocampal and/or basocortical circuits, as evidenced by our current findings in Fr Ctx. The studies conducted by Várhelyi et al, 2017 [100] and Ali et al 2021 [101] on Adipor1 and Adipor2 suggest that RNA and protein changes are not be expected by genotype and may be driven later in the DS mice by BFCN degeneration or loss of APN expression in the brain.…”

Cadmium, an Environmental Contaminant, Exacerbates Alzheimer’s Pathology in the Aged Mice’s Brain

“…The effect of environmental contaminants on ROS/oxidative stress-mediated AD pathologies and their relationship with metabolic stress should be investigated. This is because the lifestyle and brain metabolism-associated AMP-activated protein kinase (AMPK) and silent information regulator 1 (Sirt-1) signaling have a key role in maintaining cellular homeostasis and protecting the cells against external and internal stress or insults and have a protective role in AD pathologies (Shah et al, 2017 ; Gu et al, 2018 ; Yoon et al, 2018 ; Ali et al, 2021 ). AMPK act as a fuel sensor and master regulator of cellular energy and plays a vital role in stress conditions and regulates the global cellular energy homeostasis in the brain as well as in the peripheral system.…”