Selenomethionine Mitigates Cognitive Decline by Targeting Both Tau Hyperphosphorylation and Autophagic Clearance in an Alzheimer's Disease Mouse Model

Abstract

Tau pathology was recently identified as a key driver of disease progression and an attractive therapeutic target in Alzheimer's disease (AD). Selenomethionine (Se-Met), a major bioactive form of selenium (Se) in organisms with significant antioxidant capacity, reduced the levels of total tau and hyperphosphorylated tau and ameliorated cognitive deficits in younger triple transgenic AD (3xTg-AD) mice. Whether Se-Met has a similar effect on tau pathology and the specific mechanism of action in older 3xTg-AD mice remains unknown. Autophagy is a major self-degradative process to maintain cellular homeostasis and function. Autophagic dysfunction has been implicated in the pathogenesis of multiple age-dependent diseases, including AD. Modulation of autophagy has been shown to retard the accumulation of misfolded and aggregated proteins and to delay the progression of AD. Here, we found that 3xTg-AD mice showed significant improvement in cognitive ability after a 3-month treatment with Se-Met beginning at 8 months of age. In addition to attenuating the hyperphosphorylation of tau by modulating the activity of Akt/glycogen synthase kinase-3␤ and protein phosphatase 2A, Se-Met-induced reduction of tau was also mediated by an autophagy-based pathway. Specifically, Se-Met improved the initiation of autophagy via the AMP-activated protein kinase-mTOR (mammalian target of rapamycin) signaling pathway and enhanced autophagic flux to promote the clearance of tau in 3xTg-AD mice and primary 3xTg neurons. Thus, our results demonstrate for the first time that Se-Met mitigates cognitive decline by targeting both the hyperphosphorylation of tau and the autophagic clearance of tau in AD mice. These data strongly support Se-Met as a potent nutraceutical for AD therapy.

Moving to the Rhythm with Clock (Circadian) Genes, Autophagy, mTOR, and SIRT1 in Degenerative Disease and Cancer

“…Autophagy can be involved in a number of degenerative disorders such as Alzheimer's disease (42-46), Parkinson's disease (41, 47, 48), Huntington's disease (49-51), and diabetes mellitus (12, 18, 33, 43, 52, 53). Importantly, autophagy also can impact cognitive decline (12, 54, 55) and aging processes (43, 56-60).…”

“…Even mild changes in the external environment that affect circadian rhythm may alter cognition. Chronic sleep fragmentation has been shown to affect autophagy proteins in the hippocampus (64) that may affect memory and cognition (44, 46, 55, 56, 65). In addition, autophagy in the hippocampus is depressed during the absence of the PER1 circadian clock protein that may worsen the pathology of cerebral ischemia (66).…”

“…Important in the signaling cascade of mTOR is AMP activated protein kinase (AMPK). AMPK can prevent mTORC1 activity through the activation of the hamartin (tuberous sclerosis 1)/tuberin (tuberous sclerosis 2) (TSC1/TSC2) complex and can lead to the induction of autophagy (46, 58, 93-95). …”

Novel Treatment Strategies for the Nervous System: Circadian Clock Genes, Non-coding RNAs, and Forkhead Transcription Factors

“…These neural aggregates lead to behavior impairments that can be resolved with the maintenance of autophagy pathways in neurons (99). In addition, autophagy is involved in a number of degenerative disorders such as cognitive decline (14, 56, 100), AD (40, 48, 83, 101, 102), Parkinson’s disease (11, 87, 98, 103), Huntington’s disease (59, 104, 105), DM (14, 17, 40, 89, 106, 107), and aging processes (8, 40, 85, 91, 108–111). Autophagy also may be required to preserve metabolic homeostasis with mTOR (112).…”

“…It has been noted that mild changes in the external environment that affect circadian rhythm may alter cognition. Chronic sleep fragmentation has been shown to affect autophagy proteins in the hippocampus (123) that may affect memory and cognition (48, 56, 102, 124, 125). Autophagy in the hippocampus also is depressed during the absence of the PER1 circadian clock protein that may worsen the pathology of cerebral ischemia (126).…”