Background: Dementia is a neurological condition characterized by deterioration in cognitive, behavioral, social, and emotional functions. Pharmacological interventions are available but have limited effect in treating many of the disease's features. Several studies have proposed therapy with music as a possible strategy to slow down cognitive decline and behavioral changes associated with aging in combination with the pharmacological therapy. Objective: We performed a systematic review and subsequent meta-analysis to check whether the application of music therapy in people living with dementia has an effect on cognitive function, quality of life, and/or depressive state. Methods: The databases used were Medline, PubMed Central, Embase, PsycINFO, and the Cochrane Library. The search was made up of all the literature until present. For the search, key terms, such as “music,” “brain,” “dementia,” or “clinical trial,” were used. Results: Finally, a total of eight studies were included. All the studies have an acceptable quality based on the score on the Physiotherapy Evidence Database (PEDro) and Critical Appraisal Skills Program (CASP) scales. After meta-analysis, it was shown that the intervention with music improves cognitive function in people living with dementia, as well as quality of life after the intervention and long-term depression. Nevertheless, no evidence was shown of improvement of quality of life in long-term and short-term depression. Conclusion: Based on our results, music could be a powerful treatment strategy. However, it is necessary to develop clinical trials aimed to design standardized protocols depending on the nature or stage of dementia so that they can be applied together with current cognitive-behavioral and pharmacological therapies.

Increased neuroinflammatory reaction is frequently observed during normal brain aging. However, a direct link between neuroinflammation and neurodegeneration during aging has not yet been clearly shown. Here, we have characterized the age‐related hippocampal inflammatory processes and the potential relation with hippocampal neurodegeneration. The mRNA expression of the pro‐inflammatory cytokines IL‐1β and tumor necrosis factor‐α (TNF‐α), and the iNOs enzyme was significantly increased in aged hippocampus. Accordingly, numerous activated microglial cells were observed in aged rats. These cells were differentially distributed along the hippocampus, being more frequently located in the hilus and the CA3 area. The mRNA expression of somatostatin, a neuropeptide expressed by some GABAergic interneurons, and the number of somatostatin‐immunopositive cells decreased in aged rats. However, the number of hippocampal parvalbumin‐containing GABAergic interneurons was preserved. Interestingly, in aged rats, the mRNA expression of somatostatin and IL‐1β was inversely correlated and, the decrease in the number of somatostatin‐immunopositive cells was higher in the hilus of dentate gyrus than in the CA1 region. Finally, intraperitoneal chronic lipopolysaccharide (LPS) injection in young animals mimicked the age‐related hippocampal inflammation as well as the decrease of somatostatin mRNA expression. Present results strongly support the neuroinflammation as a potential factor involved in the age‐related degeneration of somatostatin GABAergic cells.

Background: Neuroinflammation and protein accumulation are characteristic hallmarks of both normal aging and age-related neurodegenerative diseases. However, the relationship between these factors in neurodegenerative processes is poorly understood. We have previously shown that proteasome inhibition produced higher neurodegeneration in aged than in young rats, suggesting that other additional age-related events could be involved in neurodegeneration. We evaluated the role of lipopolysaccharide (LPS)-induced neuroinflammation as a potential synergic risk factor for hippocampal neurodegeneration induced by proteasome inhibition. Methods: Young male Wistar rats were injected with 1 μL of saline or LPS (5 mg/mL) into the hippocampus to evaluate the effect of LPS-induced neuroinflammation on protein homeostasis. The synergic effect of LPS and proteasome inhibition was analyzed in young rats that first received 1 μL of LPS and 24 h later 1 μL (5 mg/mL) of the proteasome inhibitor lactacystin. Animals were sacrificed at different times post-injection and hippocampi isolated and processed for gene expression analysis by real-time polymerase chain reaction; protein expression analysis by western blots; proteasome activity by fluorescence spectroscopy; immunofluorescence analysis by confocal microscopy; and degeneration assay by Fluoro-Jade B staining. Results: LPS injection produced the accumulation of ubiquitinated proteins in hippocampal neurons, increased expression of the E2 ubiquitin-conjugating enzyme UB2L6, decreased proteasome activity and increased immunoproteasome content. However, LPS injection was not sufficient to produce neurodegeneration. The combination of neuroinflammation and proteasome inhibition leads to higher neuronal accumulation of ubiquitinated proteins, predominant expression of pro-apoptotic markers and increased neurodegeneration, when compared with LPS or lactacystin (LT) injection alone. Conclusions: Our results identify neuroinflammation as a risk factor that increases susceptibility to neurodegeneration induced by proteasome inhibition. These results highlight the modulation of neuroinflammation as a mechanism for neuronal protection that could be relevant in situations where both factors are present, such as aging and neurodegenerative diseases.

Summary: Dysfunctions of the ubiquitin proteasome system (UPS) have been proposed to be involved in the aetiology and/or progression of several age‐related neurodegenerative disorders. However, the mechanisms linking proteasome dysfunction to cell degeneration are poorly understood. We examined in young and aged rat hippocampus the activation of the unfolded protein response (UPR) under cellular stress induced by proteasome inhibition. Lactacystin injection blocked proteasome activity in young and aged animals in a similar extent and increased the amount of ubiquitinated proteins. Young animals activated the three UPR arms, IRE1α, ATF6α and PERK, whereas aged rats failed to induce the IRE1α and ATF6α pathways. In consequence, aged animals did not induce the expression of pro‐survival factors (chaperones, Bcl‐XL and Bcl‐2), displayed a more sustained expression of pro‐apoptotic markers (CHOP, Bax, Bak and JKN), an increased caspase‐3 processing. At the cellular level, proteasome inhibition induced neuronal damage in young and aged animals as assayed using Fluorojade‐B staining. However, degenerating neurons were evident as soon as 24 h postinjection in aged rats, but it was delayed up to 3 days in young animals. Our findings show evidence supporting age‐related dysfunctions in the UPR activation as a potential mechanism linking protein accumulation to cell degeneration. An imbalance between pro‐survival and pro‐apoptotic proteins, because of noncanonical activation of the UPR in aged rats, would increase the susceptibility to cell degeneration. These findings add a new molecular vision that might be relevant in the aetiology of several age‐related neurodegenerative disorders.