New Review !! "Signaling pathway cross talk in Alzheimer’s disease"

Signaling pathway cross talk in Alzheimer’s disease

Juan A Godoy¹, Juvenal A Rios¹, Juan M Zolezzi², Nady Braidy³ and Nibaldo C Inestrosa^13*

Abstract

Numerous studies suggest energy failure and accumulative intracellular waste play a causal role in the pathogenesis of several neurodegenerative disorders and Alzheimer’s disease (AD) in particular. AD is characterized by extracellular amyloid deposits, intracellular neurofibrillary tangles, cholinergic deficits, synaptic loss, inflammation and extensive oxidative stress. These pathobiological changes are accompanied by significant behavioral, motor, and cognitive impairment leading to accelerated mortality. Currently, the potential role of several metabolic pathways associated with AD, including Wnt signaling, 5' adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), Sirtuin 1 (Sirt1, silent mating-type information regulator 2 homolog 1), and peroxisome proliferator-activated receptor gamma co-activator 1-α (PGC-1α) have widened, with recent discoveries that they are able to modulate several pathological events in AD. These include reduction of amyloid-β aggregation and inflammation, regulation of mitochondrial dynamics, and increased availability of neuronal energy. This review aims to highlight the involvement of these new set of signaling pathways, which we have collectively termed “anti-ageing pathways”, for their potentiality in multi-target therapies against AD where cellular metabolic processes are severely impaired.

New research Article with drawings: SIRT1 Protects Dendrites, Mitochondria and Synapses from Aβ Oligomers in Hippocampal Neurons

SIRT1 Protects Dendrites, Mitochondria and Synapses from Aβ Oligomers in Hippocampal Neurons

Juan A Godoy¹, ¹Centro de Envejecimiento y Regeneración (CARE); Departamento de Biología Celular, Molecular; Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, ChileClaudio Allard¹, ¹Centro de Envejecimiento y Regeneración (CARE); Departamento de Biología Celular, Molecular; Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, ChileMacarena S Arrázola¹, ²Departamento de Biología, Facultad de Ciencias, Universidad de Tarapacá, Arica, ChileJuan M Zolezzi² and ¹Centro de Envejecimiento y Regeneración (CARE); Departamento de Biología Celular, Molecular; Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, ChileNibaldo C Inestrosa^1*

Aging is a major risk factor in the onset of neurodegenerative diseases, such as Alzheimer’s disease (AD). SIRT1, a β-NAD+-dependent histone deacetylase activity, holds great potential for promoting longevity, preventing against disease and increasing cell survival. We report here, that SIRT1 protects against the damage caused by Aβ oligomers at the level of synaptic contacts, dendritic branching and mitochondrial structure in cultured rat hippocampal neurons. Neurons overexpressing SIRT1 showed increased synaptic contacts, dendritic branching and preserved mitochondrial morphology, suggesting the prevention of the Aβ oligomer-mediated neurodegeneration. Such effects were not observed in neurons overexpressing a dominant negative form of SIRT1. The potential underlying signaling pathways involved in the SIRT1 neuroprotective mechanism are discussed in the context of the peroxisome proliferator-activated receptors (PPARs), peroxisome proliferator activated receptor co-activator 1α (PGC-1α), mTOR, and the Wnt signaling pathway. Our results suggest that SIRT1 modulation might well be a therapeutic agent to protect against neurodegenerative diseases, like AD.

Long Term Potentiation (LTP)

Proceso de plasticidad sinaptica que ocurre en la región CA1 del hipocampo. La liberación de glutamato permite la activacion de los receptores AMPA y NMDA. Estos ultimos inducen la entrada de calcio permitiendo la activación de la CamKII, la cual permite la incorporacion de mas receptores a la superficie de la espina sináptica.

The synaptic plasticity in the CA1 region in the hippocampus depend of the increase in the release of the neurotransmitter glutamate to the synaptic cleft. This induces the activation of AMPA and NMDA receptors. The NMDA receptor allows the influx of Calcium activating to CamKII to induce the incorporation of new AMPA receptors to the postsynaptic membrane increase the synaptic strenght.

La plasticité synaptique dans la région CA1 de l'hippocampe dépend de l'augmentation de la libération du neurotransmetteur glutamate de la fente synaptique. Ceci induit l'activation des récepteurs AMPA et NMDA. Le récepteur NMDA permet l'afflux de calcium pour activer CaMKII pour induire l'incorporation de nouveaux récepteurs AMPA pour augmenter la membrane post-synaptique de la force synaptique.

Non-canonical Wnt signaling / signalisation Wnt non canonique

Vía de señalización Wnt no canonica, que involucra 2 de las vias conocidas
-) Vía Wnt-calcio
=) Vía Wnt-JNK