Tauroursodeoxycholic Acid Attenuates Diet-Induced and Age-Related Peripheral Endoplasmic Reticulum Stress and Cerebral Amyloid Pathology in a Mouse Model of Alzheimer’s Disease

Abstract

BACKGROUND: Obesity and diabetes are well-established risk factors of Alzheimer’s disease (AD). In the brains of patients with AD and model mice, diabetes-related factors have been implicated in the pathological changes of AD. However, the molecular mechanistic link between the peripheral metabolic state and AD pathophysiology have remained elusive. Endoplasmic reticulum (ER) stress is known as one of the major contributors to the metabolic abnormalities in obesity and diabetes. Interventions aimed at reducing ER stress have been shown to improve the systemic metabolic abnormalities, although their effects on the AD pathology have not been extensively studied. OBJECTIVES: We examined whether interventions targeting ER stress attenuate the obesity/diabetes-induced Aβ accumulation in brains. We also aimed to determine whether ER stress that took place in the peripheral tissues or central nervous system was more important in the Aβ neuropathology. Furthermore, we explored if age-related metabolic abnormalities and Aβ accumulation could be suppressed by reducing ER stress. METHODS: APP transgenic mice (A7-Tg), which exhibit Aβ accumulation in the brain, were used as a model of AD to analyze parameters of peripheral metabolic state, ER stress, and Aβ pathology in the brain. Intraperitoneal or intracerebroventricular administration of taurodeoxycholic acid (TUDCA), a chemical chaperone, was performed in high-fat diet (HFD)-fed A7-Tg mice for ~1 month, followed by analyses at 9 months of age. Mice fed a normal diet were treated with TUDCA by drinking water for 4 months and intraperitoneally for 1 month in parallel, and analyzed at 15 months of age. RESULTS: Intraperitoneal administration of TUDCA suppressed ER stress in the peripheral tissues and ameliorated the HFD-induced obesity and insulin resistance. Concomitantly, Aβ levels in the brain were significantly reduced. In contrast, intracerebroventricular administration of TUDCA had no effect on the Aβ levels. Peripheral administration of TUDCA was also effective against the age-related obesity and insulin resistance, and markedly reduced amyloid accumulation. CONCLUSIONS: Interventions that target peripheral ER stress might be beneficial therapeutic and prevention strategies against brain Aβ pathology associated with metabolic overload and aging.

Helicobacter pylori and Alzheimer’s Disease-Related Metabolic Dysfunction: Activation of TLR4/Myd88 Inflammation Pathway from p53 Perspective and a Case Study of Low-Dose Radiation Intervention

“…TUDCA (tauroursodeoxycholic acid), an endogenous bile acid, could enhance glucose homeostasis in the streptozotocin-induced AD mice . TUDCA can also attenuate high-fat diet-induced peripheral endoplasmic reticulum stress and ameliorate the high fat diet-induced obesity and insulin resistance . Fecal DCA levels have been found decreased in AD patients but not decreased in their serum .…”

“…68 TUDCA can also attenuate high-fat dietinduced peripheral endoplasmic reticulum stress and ameliorate the high fat diet-induced obesity and insulin resistance. 69 Fecal DCA levels have been found decreased in AD patients but not decreased in their serum. 70 This may be because the cholestatic was chronically damaged in the liver.…”

ER stress and UPR in Alzheimer’s disease: mechanisms, pathogenesis, treatments

“…Taurodeoxycholic acid (TUDCA) is a chemical chaperone with the potential to reduce ER stress and is widely employed in ER stress-related cell and animal studies [ 130 ]. Ochiai and colleagues investigated the impact of ER stress suppression in obese/diabetic mouse brains with Aβ deposition [ 131 ]. They administered TUDCA intraperitoneally to APP transgenic mice under a high-fat diet (HFD) intake [ 131 ].…”

“…Ochiai and colleagues investigated the impact of ER stress suppression in obese/diabetic mouse brains with Aβ deposition [ 131 ]. They administered TUDCA intraperitoneally to APP transgenic mice under a high-fat diet (HFD) intake [ 131 ]. As a result, ER stress was suppressed while Aβ deposition and insulin resistance were markedly attenuated in brains and peripheral tissues [ 131 ].…”

“…They administered TUDCA intraperitoneally to APP transgenic mice under a high-fat diet (HFD) intake [ 131 ]. As a result, ER stress was suppressed while Aβ deposition and insulin resistance were markedly attenuated in brains and peripheral tissues [ 131 ]. Hence, the chemical chaperone TUDCA is a potential therapeutic agent that may ameliorate AD progression by diminishing ER stress.…”