Abstract
Aggregated amyloid-β protein (Aβ) and Aβ-induced neuronal apoptosis have been implicated as critical factors in the pathophysiology of Alzheimer’s disease (AD). Certain preclinical results have indicated that the increased accumulation of protein aggregates in AD-affected neurons activates the unfolded protein response (UPR), a pathological phenomenon, which predominantly mediates the aberrant endoplasmic reticulum (ER) stress and apoptotic cascades in neuronal cells. In the present study, we confirmed that Santacruzamate A (STA, a natural product isolated from a Panamanian marine cyanobacterium) attenuates Aβ protein fragment 25–35 (Aβ25–35)-induced toxicity in PC12 cells and rescues cognitive deficits in APPswe/PS1dE9 mice by enhancing ER stress tolerance. We first demonstrated the anti-apoptotic effects of STA by evaluating caspase-3 activity, annexin V/propidium iodide (PI) staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Behavioral testing of STA-treated APPswe/PS1dE9 mice showed that the pronounced memory impairments were ameliorated and that the consolidated memories were stably maintained over a 2-week period. The mechanistic studies provided evidence that STA inhibited Aβ25–35-induced UPR and ER stress by regulating the ER retention signal (KDEL) receptor, which reinforced the retention of resident chaperones in the ER lumen. Furthermore, STA regulated the expression of the mitochondrial intermembrane space assembly protein 40 (Mia40) and augmenter of liver regeneration (ALR), which ultimately attenuated the mitochondrial fission and apoptosis pathways. Together, our present findings suggest that the KDEL receptor and Mia40-ALR play a role in mitigating Aβ25–35-induced neurotoxicity, which might in turn positively regulate learning and memory. These observations support that STA may be a promising agent for reversing the progression of AD.
Highlights
Alzheimer’s disease (AD) is a slow and progressive age-related neurodegenerative disease that is characterized by debilitating memory impairments, as well as by the progressive accumulation of extensive extracellular amyloid-β protein (Aβ) plaques and intracellular neurofibrillary tangles (Mullan et al, 1992)
H, STA markedly reduced the number of apoptotic and transferase-mediated biotinylated UTP nick end labeling (TUNEL)-positive cells that were induced by Aβ protein fragment 25–35 (Aβ25–35). These results indicate that STA blocked the translocation of the membrane phospholipid phosphatidylserine and DNA fragmentation during Aβ25–35-induced apoptosis, confirming that the neuroprotective effects of STA are probably due to the inhibition of apoptotic signaling
The present study demonstrated the neuroprotective effects of STA, a carbamate derivative, against Aβ25–35-induced toxicity, as well as the relevant molecular mechanisms
Summary
Alzheimer’s disease (AD) is a slow and progressive age-related neurodegenerative disease that is characterized by debilitating memory impairments, as well as by the progressive accumulation of extensive extracellular amyloid-β protein (Aβ) plaques and intracellular neurofibrillary tangles (Mullan et al, 1992). As the disease progresses, elevated levels of Aβ are believed to induce extensive neuronal loss and cognitive function deterioration, which are hypothesized to contribute to the neurodegeneration and memory impairments that are associated with AD (Butterfield et al, 2002). In cases of aggressive or persistent Aβ deposition and impairment, if the accumulated misfolded proteins cannot be cleared to restore homeostasis, an unmitigated UPR would cause protracted ER stress, which could be lethal and trigger apoptotic cascades (Yoshida et al, 2001).
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