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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulation of amyloid-β (Aβ) peptide in the hippocampus and frontal cortex of the brain, leading to progressive cognitive decline. The endogenous bile acid tauroursodeoxycholic acid (TUDCA) is a strong neuroprotective agent in several experimental models of disease, including neuronal exposure to Aβ. Nevertheless, the therapeutic role of TUDCA in AD pathology has not yet been ascertained. Here we report that feeding APP/PS1 double-transgenic mice with diet containing 0.4 % TUDCA for 6 months reduced accumulation of Aβ deposits in the brain, markedly ameliorating memory deficits. This was accompanied by reduced glial activation and neuronal integrity loss in TUDCA-fed APP/PS1 mice compared to untreated APP/PS1 mice. Furthermore, TUDCA regulated lipid-metabolism mediators involved in Aβ production and accumulation in the brains of transgenic mice. Overall amyloidogenic APP processing was reduced with TUDCA treatment, in association with, but not limited to, modulation of γ-secretase activity. Consequently, a significant decrease in Aβ(1-40) and Aβ(1-42) levels was observed in both hippocampus and frontal cortex of TUDCA-treated APP/PS1 mice, suggesting that chronic feeding of TUDCA interferes with Aβ production, possibly through the regulation of lipid-metabolism mediators associated with APP processing. These results highlight TUDCA as a potential therapeutic strategy for the prevention and treatment of AD.

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The vasculotropic E22Q mutant of the amyloid-β (Aβ) peptide is associated with hereditary cerebral hemorrhage with amyloidosis Dutch type. The cellular mechanism(s) of toxicity and nature of the AβE22Q toxic assemblies are not completely understood. Comparative assessment of structural parameters and cell death mechanisms elicited in primary human cerebral endothelial cells by AβE22Q and wild-type Aβ revealed that only AβE22Q triggered the Bax mitochondrial pathway of apoptosis. AβE22Q neither matched the fast oligomerization kinetics of Aβ42 nor reached its predominant β-sheet structure, achieving a modest degree of oligomerization with a secondary structure that remained a mixture of β and random conformations. The endogenous molecule tauroursodeoxycholic acid (TUDCA) was a strong modulator of AβE22Q-triggered apoptosis but did not significantly change the secondary structures and fibrillogenic propensities of Aβ peptides. These data dissociate the pro-apoptotic properties of Aβ peptides from their distinct mechanisms of aggregation/fibrillization in vitro, providing new perspectives for modulation of amyloid toxicity.

Alzheimer's disease (AD) poses a huge challenge for society and health care worldwide as molecular pathogenesis of the disease is poorly understood and curative treatment does not exist. The mechanisms leading to accelerated neuronal cell death in AD are still largely unknown, but accumulation of misfolded disease-specific proteins has been identified as potentially involved. In the present review, we describe the essential role of endoplasmic reticulum (ER) in AD. Despite the function that mitochondria may play as the central major player in the apoptotic process, accumulating evidence highlights ER as a critical organelle in AD. Stress that impairs ER physiology leads to accumulation of unfolded or misfolded proteins, such as amyloid β (Aβ) peptide, the major component of amyloid plaques. In an attempt to ameliorate the accumulation of unfolded proteins, ER stress triggers a protective cellular mechanism, which includes the unfolded protein response (UPR). However, when activation of the UPR is severe or prolonged enough, the final cellular outcome is pathologic apoptotic cell death. Distinct pathways can be activated in this process, involving stress sensors such as the JNK pathway or ER chaperones such as Bip/GRP94, stress modulators such as Bcl-2 family proteins, or even stress effectors such as caspase-12. Here, we detail the involvement of the ER and associated stress pathways in AD and discuss potential therapeutic strategies targeting ER stress.

The rTg4510 mouse is a tauopathy model, characterized by massive neurodegeneration in Alzheimer's disease (AD)-relevant cortical and limbic structures, deficits in spatial reference memory, and progression of neurofibrillary tangles (NFT). In this study, we examined the role of apoptosis in neuronal loss and associated tau pathology. The results showed that DNA fragmentation and caspase-3 activation are common in the hippocampus and frontal cortex of young rTg4510 mice. These changes were associated with cleavage of tau into smaller intermediate fragments, which persist with age. Interestingly, active caspase-3 was often co-localized with cleaved tau. In vitro, fibrillar Aβ 1-42 resulted in nuclear fragmentation, caspase activation, and caspase-3-induced cleavage of tau. Notably, incubation with the antiapoptotic molecule tauroursodeoxycholic acid abrogated apoptosis-mediated cleavage of tau in rat cortical neurons. In conclusion, caspase-3-cleaved intermediate tau species occurred early in rTg54510 brains and preceded cell loss in Aβ-exposed cultured neurons. These results suggest a potential role of apoptosis in neurodegeneration.

Amyloid-β (Aβ) peptide-induced neurotoxicity is typically associated with cell death through mechanisms not entirely understood. Here, we investigated stress signaling events triggered by soluble Aβ in differentiated rat neuronal-like PC12 cells. Morphologic evaluation of apoptosis confirmed that Aβ induced nuclear fragmentation that was prevented by pre-treatment with the antiapoptotic bile acid tauroursodeoxycholic acid (TUDCA). In addition, Aβ exposure triggered an early signaling response by the endoplasmic reticulum (ER) and caspase-12-mediated apoptosis, which, however, was independent of the ER-stress pathway. Furthermore, ER stress markers, including GRP94, ATF-6α, CHOP, and eIF2α, were strongly downregulated by Aβ, independent of protein degradation, and partially restored by TUDCA. Calpain inhibition prevented caspase-12 activation and reduced levels of ATF-6α. Importantly, Aβ-induced GRP94 downregulation was related to protein secretion and partially rescued through inhibition of the secretory pathway by geldanamycin and brefeldin. In conclusion, we showed that the ER is a proximal stress sensor for soluble Aβ-induced toxicity, resulting in caspase-12 activation and cell death in PC12 neuronal cells. Moreover, ER chaperone GRP94 secretion was associated with Aβ-induced apoptotic signaling. These data provide new information linking apoptotic properties of Aβ peptide to distinct subcellular mechanisms of toxicity. Further characterization of this signaling pathway is likely to provide new perspectives for modulation of amyloid-induced apoptosis.

Amyloid-β (Aβ) peptide- induced neurotoxicity is typically associated with apoptosis. In previous studies, we have shown that tauroursodeoxycholic acid (TUDCA), an endogenous anti-apoptotic bile acid, modulates Aβ-induced apoptosis. Here, we investigated stress signaling events triggered by soluble Aβ and further explored alternative pathways of neuroprotection by TUDCA in differentiated rat neuronal-like PC12 cells. Morphologic evaluation of apoptosis confirmed that Aβ-induced nuclear fragmentation was prevented by TUDCA. In addition, Aβ exposure resulted in activation of the early stress c-Jun N-terminal kinase (JNK) pathway, JNK nuclear translocation, and caspase-2 activation. Knock-down experiments of JNK established caspase-2 as a specific downstream target of JNK in Aβ-induced apoptosis. Furthermore, active caspase-2 cleaved golgin-160 and was localized to the Golgi complex. Importantly, TUDCA abrogated Aβ-induced JNK/caspase-2 signaling. In conclusion, we show that JNK is the proximal stress sensor for soluble Aβ-induced toxicity, which translocates to the nucleus, activates caspase-2, and is strongly modulated by TUDCA in PC12 neuronal cells. Active caspase-2 cleaves golgin-160, suggesting caspase-2-dependent transduction of Aβ apoptotic signaling through the Golgi complex. These data provide new information linking apoptotic properties of Aβ peptide to distinct subcellular mechanisms of toxicity. Further characterization of this signaling pathway and exact targets of modulation are likely to provide new perspectives for modulation of amyloid-induced apoptosis by TUDCA.