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The increases in population ageing and growth are leading to a boosting in the number of people living with dementia, Alzheimer's disease (AD) being the most common cause. In spite of decades of intensive research, no cure for AD has been found yet. However, some treatments that may change disease progression and help control symptoms have been proposed. Beyond the classical hypotheses of AD etiopathogenesis, i.e., amyloid beta peptide (Aβ) accumulation and tau hyperphosphorylation, a trend in attributing a key role to other molecular mechanisms is prompting the study of different therapeutic targets. Hence, drugs designed to modulate inflammation, insulin resistance, synapses, neurogenesis, cardiovascular factors and dysbiosis are shaping a new horizon in AD treatment. Within this frame, an increase in the number of candidate drugs for disease modification treatments is expected, as well as a focus on potential combinatory multidrug strategies.The present review summarizes the latest advances in drugs targeting Aβ and tau as major contributors to AD pathophysiology. In addition, it introduces the most important drugs in clinical studies targeting alternative mechanisms thought to be involved in AD's neurodegenerative process., Competing Interests: The authors declare no conflict of interest. AC is serving as the guest editor and the editorial board member of this journal. We declare that AC had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to GP., (© 2022 The Author(s). Published by IMR Press.)

Given the highly multifactorial origin of Alzheimer's disease (AD) neuropathology, disentangling and orderly knowing mechanisms involved in sporadic onset are arduous. Nevertheless, when the elements involved are dissected into smaller pieces, the task becomes more accessible. This review aimed to describe the link between c-Jun N-terminal Kinases (JNKs), master regulators of many cellular functions, and the early alterations of AD: synaptic loss and dysregulation of neuronal transport. Both processes have a role in the posterior cognitive decline observed in AD. The manuscript focuses on the molecular mechanisms of glutamatergic, GABA, and cholinergic synapses altered by the presence of amyloid-β aggregates and hyperphosphorylated tau, as well as on several consequences of the disruption of cellular processes linked to neuronal transport that is controlled by the JNK-JIP (c-jun NH2-terminal kinase (JNK)-interacting proteins (JIPs) complex, including the transport of AβPP or autophagosomes.

After decades of research, the molecular neuropathology of Alzheimer's disease (AD) is still one of the hot topics in biomedical sciences. Some studies suggest that soluble amyloid β (Aβ) oligomers act as causative agents in the development of AD and could be initiators of its complex neurodegenerative cascade. On the other hand, there is also evidence pointing to Aβ oligomers as mere aggravators, with an arguable role in the origin of the disease. In this line of research, the relative contribution of soluble Aβ oligomers to neuronal damage associated with metabolic disorders such as Type 2 Diabetes Mellitus (T2DM) and obesity is being actively investigated. Some authors have proposed the endoplasmic reticulum (ER) stress and the induction of the unfolded protein response (UPR) as important mechanisms leading to an increase in Aβ production and the activation of neuroinflammatory processes. Following this line of thought, these mechanisms could also cause cognitive impairment. The present review summarizes the current understanding on the neuropathological role of Aβ associated with metabolic alterations induced by an obesogenic high fat diet (HFD) intake. It is believed that the combination of these two elements has a synergic effect, leading to the impairement of ER and mitochondrial functions, glial reactivity status alteration and inhibition of insulin receptor (IR) signalling. All these metabolic alterations would favour neuronal malfunction and, eventually, neuronal death by apoptosis, hence causing cognitive impairment and laying the foundations for late-onset AD (LOAD). Moreover, since drugs enhancing the activation of cerebral insulin pathway can constitute a suitable strategy for the prevention of AD, we also discuss the scope of therapeutic approaches such as intranasal administration of insulin in clinical trials with AD patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

There is growing evidence that obesity associated with type 2 diabetes mellitus (T2DM) and aging are risk factors for the development of Alzheimer's disease (AD). However, the molecular mechanisms through which obesity interacts with β-amyloid (Aβ) to promote cognitive decline remains poorly understood. Memantine (MEM), a N-methyl-D-aspartate receptor antagonist, is currently used for the treatment of AD. Nonetheless, few studies have reported its effects on genetic preclinical models of this neurodegenerative disease exacerbated with high-fat diet (HFD)-induced obesity. Therefore, the present research aims to elucidate the effects of MEM on familial AD HFD-induced insulin resistance and learning and memory impairment. Furthermore, it aspires to determine the possible underlying mechanisms that connect AD to T2DM. Wild type and APPswe/PS1dE9 mice were used in this study. The animals were fed with either chow or HFD until 6 months of age, and they were treated with MEM-supplemented water (30 mg/kg) during the last 12 weeks. Our study demonstrates that MEM improves the metabolic consequences produced by HFD in this model of familial AD. Behavioural assessments confirmed that the treatment also improves animals learning abilities and decreases memory loss. Moreover, MEM treatment improves brain insulin signalling upregulating AKT, as well as cyclic adenosine monophosphate response element binding (CREB) expression, and modulates the amyloidogenic pathway, which, in turn, reduced the accumulation of Aβ. Moreover, this drug increases the activation of molecules involved with insulin signalling in the liver, such as insulin receptor substrate 2 (IRS2), which is a key protein regulating hepatic resistance to insulin. These results provide new insight into the role of MEM not only in the occurrence of AD treatment, but also in its potential application on peripheral metabolic disorders where Aβ plays a key role, as is the case of T2DM.

The molecular basis of memory loss in Alzheimer's disease (AD), the main cause of senile dementia, is under investigation. In the present study, we have focused on the early hippocampal memory-related changes in APPswe/PS1dE9 (APP/PS1) mice, a well-established mouse model of familial AD. It is well known that molecules like cAMP response element binding (CREB) and binding protein (CBP) play a crucial role in memory consolidation. We analyzed CBP on its transcriptional activity and protein levels, finding a significant downregulation of both of them at 3-month-old mice. In addition, the downregulation of this molecule was associated with a decrease on acetylation levels of histone H3 in the hippocampus of APP/PS1 mice. Moreover, the p-CREB levels, which are important for memory acquisition at 3 months in APP/PS1 mice, were downregulated. Furthermore, we suggest that early neuroinflammation, especially due to the Tnfα gene increased expression, could also be responsible to this process of memory loss. Given all the previously mentioned results, we propose that an early suitable treatment to prevent the evolution of the disease should include a combination of drugs, including anti-inflammatories, which may decrease glial activation and Tnfα levels, and phosphodiesterase inhibitors that increase cAMP levels.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence in the brain of extracellular amyloid-β protein (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. The N-Methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptor, are essential for processes like learning and memory. An excessive activation of NMDARs has been associated with neuronal loss. The discovery of extrasynaptic NMDARs provided a rational and physiological explanation between physiological and excitotoxic actions of glutamate. Memantine (MEM), an antagonist of extrasynaptic NMDAR, is currently used for the treatment of AD jointly with acetylcholinesterase inhibitors. It has been demonstrated that MEM preferentially prevents the excessive continuous extrasynaptic NMDAR disease activation and therefore prevents neuronal cell death induced by excitotoxicity without disrupting physiological synaptic activity. The problem is that MEM has shown no clear positive effects in clinical applications while, in preclinical stages, had very promising results. The data in preclinical studies suggests that MEM has a positive impact on improving AD brain neuropathology, as well as in preventing Aβ production, aggregation, or downstream neurotoxic consequences, in part through the blockade of extrasynaptic NMDAR. Thus, the focus of this review is primarily to discuss the efficacy of MEM in preclinical models of AD, consider possible combinations of this drug with others, and then evaluate possible reasons for its lack of efficacy in clinical trials. Finally, applications in other pathologies are also considered.

The aim of the present study is to elucidate the neuronal pathways associated to NSAIDs causing a reduction of the risk and progression of Alzheimer's disease. The research was developed administering the active enantiomer of ibuprofen, dexibuprofen (DXI), in order to reduce associated gastric toxicity. DXI was administered from three to six-month-old female APPswe/PS1dE9 mice as a model of familial Alzheimer's disease. DXI treatment reduced the activation of glial cells and the cytokine release involved in the neurodegenerative process, especially TNFα. Moreover, DXI reduced soluble β-amyloid (Aβ1-42) plaque deposition by decreasing APP, BACE1 and facilitating Aβ degradation by enhancing insulin-degrading enzyme. DXI also decreased TAU hyperphosphorylation inhibiting c-Abl/CABLES/p-CDK5 activation signal pathway and prevented spatial learning and memory impairment in transgenic mice. Therefore, chronic DXI treatment could constitute a potential AD-modifying drug, both restoring cognitive functions and reversing multiple brain neuropathological hallmarks., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: The sporadic and late-onset form of Alzheimer's disease (AD) constitutes the most common form of dementia. This non-familiar form could be a consequence of metabolic syndrome, characterized by obesity and the development of a brain-specific insulin resistance known as type III diabetes. This work demonstrates the development of a significant AD-like neuropathology due to these metabolic alterations., Methods: C57BL/6J mice strain were divided into two groups, one fed with a diet rich in palmitic acid (high-fat diet, HFD) since their weaning until 16 months of age, and another group used as a control with a regular diet. The analyses were carried out in the dentate gyrus area of the hippocampus using a Thioflavin-S stain and immunofluorescence assays., Results: The most significant finding of the present research was that HFD induced the deposition of the βA peptide. Moreover, the diet also caused alterations in different cell processes, such as increased inflammatory reactions that lead to a decrease in the neuronal precursor cells. In addition, the results show that there were also dysregulations in normal autophagy and apoptosis, mechanisms related to βA formation., Conclusions: The present findings confirm that HFD favors the formation of βA depositions in the brain, a key feature of AD, supporting the metabolic hypothesis of sporadic AD., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Alzheimer's disease (AD) is currently an incurable aging-related neurodegenerative disorder. Recent studies give support to the hypotheses that AD should be considered as a metabolic disease. The present study aimed to explore the relationship between hippocampal neuropathological amyloid-β (Aβ) plaque formation and obesity at an early presymptomatic disease stage (3 months of age). For this purpose, we used APPswe/PS1dE9 (APP/PS1) transgenic mice, fed with a high-fat diet (HFD) in order to investigate the potential molecular mechanisms involved in both disorders. The results showed that the hippocampus from APP/PS1 mice fed with a HFD had an early significant decrease in Aβ signaling pathway specifically in the insulin degrading enzyme protein levels, an enzyme involved in (Aβ) metabolism, and α-secretase. These changes were accompanied by a significant increase in the occurrence of plaques in the hippocampus of these mice. Furthermore, APP/PS1 mice showed a significant hippocampal decrease in PGC-1α levels, a cofactor involved in mitochondrial biogenesis. However, HFD does not provoke changes in neither insulin receptors gene expression nor enzymes involved in the signaling pathway. Moreover, there are no changes in any enzymes (kinases) involved in tau phosphorylation, such as CDK5, and neither in brain oxidative stress production. These results suggest that early changes in brains of APP/PS1 mice fed with a HFD are mediated by an increase in Aβ1 ‒ 42, which induces a decrease in PKA levels and alterations in the p-CREB/ NMDA2B /PGC1-α pathway, favoring early AD neuropathology in mice.

Alzheimer's disease (AD) currently presents one of the biggest healthcare issues in the developed countries. There is no effective treatment capable of slowing down disease progression. In recent years the main focus of research on novel pharmacotherapies was based on the amyloidogenic hypothesis of AD, which posits that the beta amyloid (Aβ) peptide is chiefly responsible for cognitive impairment and neuronal death. The goal of such treatments is (a) to reduce Aβ production through the inhibition of β and γ secretase enzymes and (b) to promote dissolution of existing cerebral Aβ plaques. However, this approach has proven to be only modestly effective. Recent studies suggest an alternative strategy centred on the inhibition of the downstream Aβ signalling, particularly at the synapse. Aβ oligomers may cause aberrant N-methyl-D-aspartate receptor (NMDAR) activation postsynaptically by forming complexes with the cell-surface prion protein (PrPC). PrPC is enriched at the neuronal postsynaptic density, where it interacts with Fyn tyrosine kinase. Fyn activation occurs when Aβ is bound to PrPC-Fyn complex. Fyn causes tyrosine phosphorylation of the NR2B subunit of metabotropic glutamate receptor 5 (mGluR5). Fyn kinase blockers masitinib and saracatinib have proven to be efficacious in treating AD symptoms in experimental mouse models of the disease.

Recent studies suggest that the neurobiology of Alzheimer's disease (AD) pathology could not be explained solely by an increase in beta-amyloid levels. In fact, success with potential therapeutic drugs that inhibit the generation of beta amyloid has been low. Therefore, due to therapeutic failure in recent years, the scientists are looking for alternative hypotheses to explain the causes of the disease and the cognitive loss. Accordingly, alternative hypothesis propose a link between AD and peripheral metabolic alteration. Then, we review in depth changes related to insulin signalling and energy metabolism in the context of the APPSwe/PS1dE9 (APP/PS1) mice model of AD. We show an integrated view of the changes that occur in the early stages of the amyloidogenic process in the APP/PS1 double transgenic mice model. These early changes affect several key metabolic processes related to glucose uptake and insulin signalling, cellular energy homeostasis, mitochondrial biogenesis and increased Tau phosphorylation by kinase molecules like mTOR and Cdk5.

Leptin (Lep) is emerging as a pivotal molecule involved in both the early events and the terminal phases of Alzheimer's disease (AD). In the canonical pathway, Lep acts as an anorexigenic factor via its effects on hypothalamic nucleus. However, additional functions of Lep in the hippocampus and cortex have been unravelled in recent years. Early events in the sporadic form of AD likely involve cellular level alterations which can have an effect on food intake and metabolism. Thus, AD can be conceivably interpreted as a multiorgan pathology that not only results in a dramatic neuronal loss in brain areas such as the hippocampus and the cortex (ultimately leading to a significant cognitive impairment) but as a disease which also affects body-weight homeostasis. According to this view, body-weight control disruptions are to be expected in both the early- and late-stage AD, concomitant with changes in serum Lep content, alterations in Lep transport across the blood-brain barrier (BBB) and Lep receptor-related signalling abnormalities. Lep is a member of the adipokine family of molecules, while the Lep receptor belongs to the class I cytokine receptors. Since cellular response to adipokine signalling can be either potentiated or diminished as a result of specific ligand-receptor interactions, Lep interactions with other members of the adipokine family including amylin, ghrelin and hormones such as prolactin require further investigation. In this review, we provide a general perspective on the functions of Lep in the brain, with a particular focus on the sporadic AD.

Alzheimer's disease (AD) is a degenerative neurological disorder that is the most common cause of dementia and disability in older patients. Available treatments are symptomatic in nature and are only sufficient to improve the quality of life of AD patients temporarily. A potential strategy, currently under investigation, is to target cell-signaling pathways associated with neurodegeneration, in order to decrease neuroinflammation, excitotoxicity, and to improve cognitive functions. Current review centers on the role of neuroinflammation and the specific contribution of mast cells to AD pathophysiology. The authors look at masitinib therapy and the evidence presented through preclinical and clinical trials. Dual actions of masitinib as an inhibitor of mast cell-glia axis and a Fyn kinase blocker are discussed in the context of AD pathology. Masitinib is in Phase III clinical trials for the treatment of malignant melanoma, mastocytosis, multiple myeloma, gastrointestinal cancer and pancreatic cancer. It is also in Phase II/III clinical trials for the treatment of multiple sclerosis, rheumatoid arthritis and AD. Additional research is warranted to better investigate the potential effects of masitinib in combination with other drugs employed in AD treatment.

A growing body of evidence suggests that β-amyloid peptides (Aβ) are unlikely to be the only factor involved in Alzheimer's disease (AD) aetiology. In fact, a strong correlation has been established between AD patients and patients with type 2 diabetes and/or cholesterol metabolism alterations. In addition, a link between adipose tissue metabolism, leptin signalling in particular, and AD has also been demonstrated. In the present study we analyzed the expression of molecules related to metabolism, with the main focus on leptin and prolactin signalling pathways in an APPswe/PS1dE9 (APP/PS1) transgenic mice model, at 3 and 6 months of age, compared to wild-type controls. We have chosen to study 3 months-old APP/PS1 animals at an age when neither the cognitive deficits nor significant Aβ plaques in the brain are present, and to compare them to the 6 months-old mice, which exhibit elevated levels of Aβ in the hippocampus and memory loss. A significant reduction in both mRNA and protein levels of the prolactin receptor (PRL-R) was detected in the hippocampi of 3 months old APP/PS1 mice, with a decrease in the levels of the leptin receptor (OB-R) first becoming evident at 6 months of age. We proceeded to study the expression of the intracellular signalling molecules downstream of these receptors, including stat (1-5), sos1, kras and socs (1-3). Our data suggest a downregulation in some of these molecules such as stat-5b and socs (1-3), in 3 months-old APP/PS1 brains. Likewise, at the same age, we detected a significant reduction in mRNA levels of lrp1 and cyp46a1, both of which are involved in cholesterol homeostasis. Taken together, these results demonstrate a significative impairment in adipokine receptors signalling and cholesterol regulation pathways in the hippocampus of APP/PS1 mice at an early age, prior to the Aβ plaque formation.

Aims: The cholinergic system is one of the neurotransmitter systems altered in Alzheimer's disease (AD), the most common form of human dementia. The objective of this work was to determine the REST/NRSF involvement in altered ChAT expression in the neocortex and hippocampus of an AD transgenic mouse (homozygous 3xTg-AD) that over-expresses 3 proteins, amyloid-β precursor protein, presenilin-1, and tau, all of which are associated with AD and cause cellular degeneration., Main Methods: Two groups (WT and 3xTg-AD) of 11-month-old female mice were analyzed and compared. Half of the brains of each group were used for ChAT immunohistochemistry, and Western Blot analyses of ChAT and REST/NRSF were performed on the other half., Key Findings: We observed significant decreases in the number of ChAT-immunoreactive cells in the Meynert nucleus and of fibers in the frontal motor cortex and hippocampal CA1 area in transgenic mice compared with control mice. An increased level of REST/NRSF protein and a reduction of ChAT protein expression in the 3xTg-AD mice compared with their controls were also found in both in the latter two cerebral regions., Significance: The increased REST/NRSF expression reported here and its effect on the regulatory region for ChAT transcription could explain the decreased expression of ChAT in the 3xTg-AD mouse; these findings may be associated with the degeneration observed in AD., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The present study had focused on the behavioral phenotype and gene expression profile of molecules related to insulin receptor signaling in the hippocampus of 3 and 6 month-old APPswe/PS1dE9 (APP/PS1) transgenic mouse model of Alzheimer's disease (AD). Elevated levels of the insoluble Aβ (1-42) were detected in the brain extracts of the transgenic animals as early as 3 months of age, prior to the Aβ plaque formation (pre-plaque stage). By the early plaque stage (6 months) both the soluble and insoluble Aβ (1-40) and Aβ (1-42) peptides were detectable. We studied the expression of genes related to memory function (Arc, Fos), insulin signaling, including insulin receptor (Insr), Irs1 and Irs2, as well as genes involved in insulin growth factor pathways, such as Igf1, Igf2, Igfr and Igfbp2. We also examined the expression and protein levels of key molecules related to energy metabolism (PGC1-α, and AMPK) and mitochondrial functionality (OXPHOS, TFAM, NRF1 and NRF2). 6 month-old APP/PS1 mice demonstrated impaired cognitive ability, were glucose intolerant and showed a significant reduction in hippocampal Insr and Irs2 transcripts. Further observations also suggest alterations in key cellular energy sensors that regulate the activities of a number of metabolic enzymes through phosphorylation, such as a decrease in the Prkaa2 mRNA levels and in the pAMPK (Thr172)/Total APMK ratio. Moreover, mRNA and protein analysis reveals a significant downregulation of genes essential for mitochondrial replication and respiratory function, including PGC-1α in hippocampal extracts of APP/PS1 mice, compared to age-matched wild-type controls at 3 and 6 months of age. Overall, the findings of this study show early alterations in genes involved in insulin and energy metabolism pathways in an APP/PS1 model of AD. These changes affect the activity of key molecules like NRF1 and PGC-1α, which are involved in mitochondrial biogenesis. Our results reinforce the hypothesis that the impairments in both insulin signaling and energy metabolism precede the development of AD amyloidogenesis., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The neuroinflammatory process is thought to contribute to the progression of neurological disorders and brain pathologies. The release of pro-inflammatory cytokines and chemokines by activated glial cells, astrocytes and microglia plays an important role in this process. However, the role of hypoxia-inducible factor-1α (HIF-1α), the key transcription factor regulating the expression of hypoxia-inducible genes, during glial activation is less known. Thus, we examined the significance of HIF-1α in three experimental models: first in an acute model of inflammation induced by pro-inflammatory cytokines TNF-α, IL-1β and IFN-γ; secondly, in a chronic model of inflammation using an APPswe/PS1dE9 (APP/PS1) transgenic mouse model of Alzheimer's disease and thirdly via the inhibition of the PI3K/AKT pathway in a model of neuronal apoptosis. During acute glial inflammation induced by in vitro administration of TNF-α, IL-1β and IFN-γ, mRNA expression levels of HIF-1α were significantly upregulated; however, this effect was blocked by SP600126, a pharmacological inhibitor of mitogen-activated protein kinases (MAPKs). These data suggest that MAPKs could be involved in HIF-1α regulation. In addition, we observed that HIF-1α is not involved in the neuronal apoptotic process mediated by PI3-kinase inhibition, which is regulated by c-Jun. Finally, we did not detect significant differences in the expression of HIF-1α mRNA in APP/PS1 mice during the course of the study (3-12 months of age). Thus, we demonstrated that HIF-1α has a prominent role in acute but not in chronic inflammatory processes, such as the one which occurs in the APP/PS1 experimental model of AD. Moreover, HIF-1α is not involved in neuronal apoptosis after PI3K/AKT inhibition., (Copyright © 2013 Elsevier Ltd. All rights reserved.)