Role of Serotonylation and SERT Posttranslational Modifications in Alzheimer's Disease Pathogenesis.

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) is implicated mainly in Alzheimer's disease (AD) and reported to be responsible for several processes and roles in the human body, such as regulating sleep, food intake, sexual behavior, anxiety, and drug abuse. It is synthesized from the amino acid tryptophan. Serotonin also functions as a signal between neurons to mature, survive, and differentiate. It plays a crucial role in neuronal plasticity, including cell migration and cell contact formation. Various psychiatric disorders, such as depression, schizophrenia, autism, and Alzheimer's disease, have been linked to an increase in serotonin-dependent signaling during the development of the nervous system. Recent studies have found 5-HT and other monoamines embedded in the nuclei of various cells, including immune cells, the peritoneal mast, and the adrenal medulla. Evidence suggests these monoamines to be involved in widespread intracellular regulation by posttranslational modifications (PTMs) of proteins. Serotonylation is the calcium-dependent process in which 5-HT forms a long-lasting covalent bond to small cytoplasmic G-proteins by endogenous transglutaminase 2 (TGM2). Serotonylation plays a role in various biological processes. The purpose of our article is to summarize historical developments and recent advances in serotonin research and serotonylation in depression, aging, AD, and other age-related neurological diseases. We also discussed several of the latest developments with Serotonin, including biological functions, pathophysiological implications and therapeutic strategies to treat patients with depression, dementia, and other age-related conditions.

A partial reduction of VDAC1 enhances mitophagy, autophagy, synaptic activities in a transgenic Tau mouse model.

Alzheimer's disease (AD) is the most common cause of mental dementia in the aged population. AD is characterized by the progressive decline of memory and multiple cognitive functions, and changes in behavior and personality. Recent research has revealed age-dependent increased levels of VDAC1 in postmortem AD brains and cerebral cortices of APP, APPxPS1, and 3xAD.Tg mice. Further, we found abnormal interaction between VDAC1 and P-Tau in the AD brains, leading to mitochondrial structural and functional defects. Our current study aimed to understand the impact of a partial reduction of voltage-dependent anion channel 1 (VDAC1) protein on mitophagy/autophagy, mitochondrial and synaptic activities, and behavior changes in transgenic TAU mice in Alzheimer's disease. To determine if a partial reduction of VDAC1 reduces mitochondrial and synaptic toxicities in transgenic Tau (P301L) mice, we crossed heterozygote VDAC1 knockout (VDAC1+/- ) mice with TAU mice and generated double mutant (VDAC1+/- /TAU) mice. We assessed phenotypic behavior, protein levels of mitophagy, autophagy, synaptic, other key proteins, mitochondrial morphology, and dendritic spines in TAU mice relative to double mutant mice. Partial reduction of VDAC1 rescued the TAU-induced behavioral impairments such as motor coordination and exploratory behavioral changes, and learning and spatial memory impairments in VDAC1+/- /TAU mice. Protein levels of mitophagy, autophagy, and synaptic proteins were significantly increased in double mutant mice compared with TAU mice. In addition, dendritic spines were significantly increased; the mitochondrial number was significantly reduced, and mitochondrial length was increased in double mutant mice. Based on these observations, we conclude that reduced VDAC1 is beneficial in symptomatic-transgenic TAU mice.

MicroRNA-455-3p improves synaptic, cognitive functions and extends lifespan: Relevance to Alzheimer's disease.

BACKGROUND: MicroRNA-455-3p is one of the highly conserved miRNAs involved in multiple cellular functions in humans and we explored its relevance to learning and memory functions in Alzheimer's disease (AD). Our recent in vitro studies exhibited the protective role of miR-455-3p against AD toxicities in reducing full-length APP and amyloid-ß (Aß) levels, and also in reducing defective mitochondrial biogenesis, impaired mitochondrial dynamics and synaptic deficiencies. In the current study, we sought to determine the function of miR-455-3p in mouse models. METHODS: For the first time we generated both transgenic (TG) and knockout (KO) mouse models of miR-455-3p. We determined the lifespan extension, cognitive function, mitochondrial biogenesis, mitochondrial dynamics, mitochondrial morphology, dendritic spine density, synapse numbers and synaptic activity in miR-455-3p TG and KO mice. RESULTS: MiR-455-3p TG mice lived 5 months longer than wild-type (WT) counterparts, whereas KO mice lived 4 months shorter than WT mice. Morris water maze test showed improved cognitive behavior, spatial learning and memory in miR-455-3p TG mice relative to age-matched WT mice and miR-455-3p KO mice. Further, mitochondrial biogenesis, dynamics and synaptic activities were enhanced in miR-455-3p TG mice, while these were reduced in KO mice. Overall, overexpressed miR-455-3p in mice displayed protective effects, whereas depleted miR-455-3p in mice exhibited deleterious effects in relation to lifespan, cognitive behavior, and mitochondrial and synaptic activities. CONCLUSION: Both mouse models could be ideal research tools to understand the molecular basis of aging and its relevance to AD and other age-related diseases.