Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive impairment that increasingly afflicts the elderly population. Soluble oligomers (AβOs) has been implicated in AD pathogenesis: however, the molecular events underlying a role for Aβ are not well understood. We studied the effects of AβOs on mitochondrial function and on key proteins that regulate mitochondrial dynamics and biogenesis in hippocampal neurons and PC-12 cells. We find that AβOs treatment caused a reduction in total Mfn1 after a 2 h exposure (42 ± 11%); while DRP1 increased at 1 and 2 h (205 ± 22% and 198 ± 27%, respectively), correlating to changes in mitochondrial morphology. We also observed that SIRT1 levels were reduced after acute and chronic AβOs treatment (68 ± 7% and 77 ± 6%, respectively); while PGC-1α levels were reduced with the same time treatments (68 ± 8% and 67 ± 7%, respectively). Interestingly, we found that chronic treatment with AβOs increased the levels of pSIRT1 (24 h: 157 ± 18%), and we observed changes in the PGC-1α and p-SIRT1 nucleus/cytosol ratio and SIRT1-PGC-1α interaction pattern after chronic exposure to AβOs. Our data suggest that AβOs induce important changes in the level and localization of mitochondrial proteins related with the loss of mitochondrial function that are mediated by a fast and sustained SIRT1/PGC-1α complex disruption promoting a “non-return point” to an irreversible synaptic failure and neuronal network disconnection.

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by cognitive impairment that increasingly affects the elderly. AD's main features have been related to cellular and molecular events, including the aberrant aggregation of the amyloid beta peptide (Aβ), Ca²⁺ dyshomeostasis, and increased mitochondria-associated membranes (MAMs). Transglutaminase type 2 (TG2) is a ubiquitous enzyme whose primary role is the Ca²⁺-dependent proteins transamidation, including the Aβ peptide. TG2 activity has been closely related to cellular damage and death. We detected increased TG2 levels in neuronal cells treated with Aβ oligomers (AβOs) and hippocampal slices from J20 mice using cellular and molecular approaches. In this work, we characterized the capacity of TG2 to interact and promote Aβ toxic aggregates (AβTG2). AβTG2 induced an acute increase in intracellular Ca²⁺, miniature currents, and hiperexcitability, consistent with an increased mitochondrial Ca²⁺ overload, IP3R-VDAC tethering, and mitochondria-endoplasmic reticulum contacts (MERCs). AβTG2 also decreased neuronal viability and excitatory postsynaptic currents, reinforcing the idea of synaptic failure associated with MAMs dysregulation mediated by TG2. Z-DON treatment, TG2 inhibitor, reduced calcium overload, mitochondrial membrane potential loss, and synaptic failure, indicating an involvement of TG2 in a toxic cycle which increases Aβ aggregation, Ca²⁺ overload, and MAMs upregulation. These data provide novel information regarding the role TG2 plays in synaptic function and contribute additional evidence to support the further development of TG2 inhibitors as a disease-modifying strategy for AD.

Several studies have pointed to soluble oligomers of beta amyloid peptide (SOAβ) as the principal neurotoxic agents responsible for the generation of synaptotoxic events that can explain the main symptoms of Alzheimer’s disease (AD). Among the toxic features associated with SOAβ, one of the most notorious is the formation of a non-selective pore-like structure in the plasma membrane, which may partly explain the overload of intracellular Ca²⁺. There is evidence that the pore causes leakage of key intracellular compounds, such as adenosine triphosphate (ATP), to the extracellular milieu. Extracellular ATP activates P2X receptors (P2XR), which are ligand-gated ion channels (LGICs) widely expressed in both neuron and glial cells and act as neuromodulators of synaptic activity by promoting Ca²⁺ entry and facilitating neurotransmitter release. There is abundant evidence correlating the overexpression of these receptors to neurodegenerative diseases, including AD, thus opening the possibility that P2XR could potentiate the toxic mechanisms induced by SOAβ and contribute to intracellular Ca²⁺ overload in neurons and other mechanisms related to glial activation and inflammation. In this review, we correlate scientific evidence related to the main toxic effects induced by SOAβ and those that are mediated by purinergic P2XR. The data suggest that these purinergic receptors participate in the deleterious cellular and molecular effects of SOAβ that lead to the pathogenesis of AD. This information sheds light on the participation of new components in SOAβ toxicity that could be interesting as pharmacological targets for the development of molecular or chemical compounds able to modulate them.

Alzheimer’s disease (AD) is a neurodegenerative pathology, which is characterized by progressive and irreversible cognitive impairment. Most of the neuronal perturbations described in AD can be associated with soluble amyloid– β oligomers (SO-Aβ ). T

Garlic has been used for decades as an important food and additionally for its beneficial properties in terms of nutrition and ancestral therapeutics. In this work, we compare the properties of fresh (WG) and aged (BG) extract obtained from elephant garlic, harvested on Chiloe Island, Chile. BG was prepared from WG with a 20-day aging process under controlled temperature and humidity conditions. We observed that in BG, compounds such as diallyl disulfide decrease, and compounds of interest such as 5-hydroxymethylfurfural (69%), diallyl sulfide (17%), 3H-1,2-Dithiole (22%) and 4-Methyl-1,2,3-trithiolane (16%) were shown to be increased. Using 2,2-diphenyl-1-picrylhydrazyl (DPPH, BG: 51 ± 5.7%, WG: 12 ± 2.6%) and 2,20-azino-bis-(3-ethylbenzothiazoline-6 sulfonate) diammonium salt (ABTS, BG: 69.4 ± 2.3%, WG: 21 ± 3.9%) assays, we observed that BG possesses significantly higher antioxidant activity than WG and increased cell viability in hippocampal slices (41 ± 9%). The effects of WG and BG were shown to improve the neuronal function through an increased in intracellular calcium transients (189 ± 4%). In parallel, BG induced an increase in synaptic vesicle protein 2 (SV-2; 75 ± 12%) and brain-derived neurotrophic factor (BDNF; 32 ± 12%) levels. Thus, our study provides the initial scientific bases to foster the use of BG from Chiloe Island as a functional food containing a mixture of bioactive compounds that may contribute to brain health and well-being.