Epigallocatechin-3-gallate (EGCG), a
catechin found in
green tea, has been previously investigated for its
neuroprotective effects in vitro and in vivo. In the present study, we aimed to evaluate its possible beneficial effects in a well-established preclinical mixed model of familial
Alzheimer's disease (AD) and
type 2 diabetes mellitus (T2DM) based on the use of transgenic APPswe/PS1dE9 (APP/PS1) mice fed with a high fat diet (HFD). C57BL/6 wild-type (WT) and APP/PS1 mice were used in this study. APP/PS1 mice were fed with a
palmitic acid-enriched HFD (APP/PS1 HFD) containing 45% of fat mainly from hydrogenated
coconut oil. Intraperitoneal
glucose tolerance tests (IP-GTT) and
insulin tolerance tests (IP-ITT) were performed. Western blot analyses were performed to analyse
protein expression, and water maze and novel object recognition test were done to evaluate the cognitive process. EGCG treatment improves peripheral parameters such as
insulin sensitivity or liver
insulin pathway signalling, as well as central
memory deficits. It also markedly increased synaptic markers and cAMP response element binding (CREB) phosphorylation rates, as a consequence of a decrease in the unfolded protein response (UPR) activation through the reduction in the activation factor 4 (ATF4) levels and posterior downregulation of
protein tyrosine phosphatase 1B (PTP1B). Moreover, EGCG significantly decreased brain
amyloid β (Aβ) production and plaque burden by increasing the levels of α-
secretase (ADAM10). Also, it led to a reduction in
neuroinflammation, as suggested by the decrease in astrocyte reactivity and
toll-like receptor 4 (TLR4) levels. Collectively, evidence suggests that chronic EGCG prevents distinct neuropathological AD-related hallmarks. This study also provides novel insights into the metabolic and neurobiological mechanisms of EGCG against cognitive loss through its effects on UPR function, suggesting that this compound may be a promising disease-modifying treatment for
neurodegenerative diseases.