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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the progressive deterioration of cognitive functions. Cortical and hippocampal hyperexcitability intervenes in the pathological derangement of brain activity leading to cognitive decline. As key regulators of neuronal excitability, the voltage-gated K + channels (K V ) might play a crucial role in the AD pathophysiology. Among them, the K V 2.1 channel, the main α subunit mediating the delayed rectifier K + currents (I DR ) and controlling the intrinsic excitability of pyramidal neurons, has been poorly examined in AD. In the present study, we investigated the K V 2.1 protein expression and activity in hippocampal neurons from the Tg2576 mouse, a widely used transgenic model of AD. To this aim we performed whole-cell patch-clamp recordings, Western blotting, and immunofluorescence analyses. Our Western blotting results reveal that K V 2.1 was overexpressed in the hippocampus of 3-month-old Tg2576 mice and in primary hippocampal neurons from Tg2576 mouse embryos compared with the WT counterparts. Electrophysiological experiments unveiled that the whole I DR were reduced in the Tg2576 primary neurons compared with the WT neurons, and that this reduction was due to the loss of the K V 2.1 current component. Moreover, we found that the reduction of the K V 2.1-mediated currents was due to increased channel clustering, and that glutamate, a stimulus inducing K V 2.1 declustering, was able to restore the I DR to levels comparable to those of the WT neurons. These findings add new information about the dysregulation of ionic homeostasis in the Tg2576 AD mouse model and identify K V 2.1 as a possible player in the AD-related alterations of neuronal excitability.

Recent findings in the understanding of amyotrophic lateral sclerosis (ALS) revealed that alteration in calcium (Ca 2+ ) homeostasis may largely contribute to motor neuron demise. A large part of these alterations is due to dysfunctional Ca 2+ -storing organelles, including the endoplasmic reticulum (ER) and mitochondria. Very recently, lysosomal Ca 2+ dysfunction has emerged as an important pathological change leading to neuronal loss in ALS. Remarkably, the Ca 2+ -storing organelles are interacting with each other at specialized domains controlling mitochondrial dynamics, ER/lysosomal function, and autophagy. This occurs as a result of interaction between specific ionic channels and Ca 2+ -dependent proteins located in each structure. Therefore, the dysregulation of these ionic mechanisms could be considered as a key element in the neurodegenerative process. This review will focus on the possible role of lysosomal Ca 2+ dysfunction in the pathogenesis of several neurodegenerative diseases, including ALS and shed light on the possibility that specific lysosomal Ca 2+ channels might represent new promising targets for preventing or at least delaying neurodegeneration in ALS., Competing Interests: The authors declare no conflicts of interests.