Current Alzheimer Research - Volume 17, Issue 14, 2020

Background: Dementia and its related types such as Alzheimer’s disease, vascular dementia and mixed dementia belong to brain associated diseases, resulting in long-term progressive memory loss. These diseases are so severe that can affect a person's daily routine. Up to date, treatment of dementia is still an unmet challenge due to their complex pathophysiology and unavailable efficient pharmacological approaches. The use of nanotechnology based pharmaceutical products could possibly improve the management of dementia given that nanocarriers could more efficiently deliver drugs to the brain. Objective: The objective of this study is to provide the current nanotechnology based drug delivery systems for the treatment of various dementia types. In addition, the current diagnosis biomarkers for the mentioned dementia types along with their available pharmacological treatment are being discussed. Methods: An extensive review of the current nanosystems such as brain drug delivery systems against Alzheimer’s disease, vascular dementia and mixed dementia was performed. Moreover, nanotheranostics as possible imaging markers for such dementias were also reported. Results: The field of nanotechnology is quite advantageous for targeting dementia given that nanoscale drug delivery systems easily penetrate the blood brain barrier and circulate in the body for prolonged time. These nanoformulations consist of polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, microemulsions, nanoemulsions, and liquid crystals. The delivery of the nanotherapeutics can be achieved via various administration routes such as transdermal, injectable, oral, and more importantly, through the intranasal route. Nonetheless, the nanocarriers are mostly limited to Alzheimer’s disease targeting; thus, nanocarriers for other types of dementia should be developed. Conclusion: To conclude, understanding the mechanism of neurodegeneration and reviewing the current drug delivery systems for Alzheimer’s disease and other dementia types are significant for medical and pharmaceutical society to produce efficient therapeutic choices and novel strategies based on multifunctional and biocompatible nanocarriers, which can deliver the drug sufficiently into the brain.

Receptor for Advanced Glycation End product (RAGE) plays a crucial role in a variety of physiological and pathological processes due to its ability to bind a broad repertory of ligands. There are also multiple forms of RAGE that exist; some work on promoting feed-forward pathways while others perform inhibitory actions. This review focuses on the RAGE isoforms expression, its intracellular pathways activation via RAGE- ligand interaction, and its importance in the physiological and pathological process of the brain. Many studies have suggested that RAGE induces the pathophysiological changes in Alzheimer’s disease (AD) by being an intermediator of inflammation and inducer of oxidative stress. The critical roles played by RAGE in AD include its involvement in amyloid-beta (Aβ) production, clearance, synaptic impairment, and neuronal circuit dysfunction. RAGE-Aβ interaction also mediates the bi-directional crosstalk between peripheral and central systems. This interaction underlies a potential molecular pathway that disrupts the material structure and physiology of the brain. This review highlights the structure-function relation for RAGEAβ interaction and the role of RAGE as a potential target in the development of treatments for AD.

Alzheimer’s disease (AD) is a persistent neuropathological stipulation manifested in the form of neuronal/synapse demise, the formation of senile plaques, hyperphosphorylated tau tangles, neuroinflammation, and apoptotic cell death. The absence of a therapeutic breakthrough for AD has continued the quest to find a suitable intervention. Apart from various candidates, the cyclic AMPprotein kinase A-cAMP response element-binding protein (cAMP/PKA/CREB) pathway is the most sought-after drug target AD as the bulk of quality literature documents that there is downregulation of cAMP signaling and CREB mediated transcriptional cascade in AD. cAMP signaling is evolutionarily conserved and can be found in all species. cAMP response element-binding protein (CREB) is a ubiquitous and integrally articulated transcription aspect that regulates neuronal growth, neuronal differentiation/ proliferation, synaptic plasticity, neurogenesis, maturation of neurons, spatial memory, longterm memory formation as well as ensures neuronal survival. CREB is a central part of the molecular machinery that has a role in transforming short-term memory to long-term. Besides AD, impairment of CREB signaling has been well documented in addiction, Parkinsonism, schizophrenia, Huntington’s disease, hypoxia, preconditioning effects, ischemia, alcoholism, anxiety, and depression. The current work highlights the role and influence of CREB mediated transcriptional signaling on major pathological markers of AD (amyloid β, neuronal loss, inflammation, apoptosis, etc.). The present work justifies the continuous efforts being made to explore the multidimensional role of CREB and related downstream signaling pathways in cognitive deficits and neurodegenerative complications in general and AD particularly. Moreover, it is reaffirmed that cyclic nucleotide signaling may have vast potential to treat neurodegenerative complications like AD.

Background: Alzheimer’s disease (AD) has challenged single-target therapeutic strategies, raising the possibility that combined therapies may offer a more effective treatment strategy. Objective: There is substantial evidence for the efficacy of leptin (L) (neuroprotective hormone) and pioglitazone (P) (anti-inflammatory agent) as monotherapies in AD. We have previously shown that combination treatment of L+P in APP/PS1 mice at the onset of pathology significantly improved memory and reduced brain Aβ levels relative to control mice. In this new study, we sought to replicate our previous findings in a new cohort of APP/PS1 mice to further confirm whether the combined treatment of L+P is superior to each treatment individually. Methods: We have re-evaluated the effects of L+P co-treatment in APP/PS1 mice using thioflavin-S staining, MOAβ immunolabeling, and enzyme-linked immunosorbent assay (ELISA) to examine effects on Aβ levels and pathology, relative to animals that received L or P individually. Results: We demonstrated that a combination of L and P significantly enhances the anti-Aβ effect of L or P in the hippocampus of APP/PS1 mice. Conclusion: Our findings suggest that combining L and P significantly enhances the anti-Aβ effect of L or P in the hippocampus of APP/PS1 mice and maybe a potential new effective strategy for AD therapy.

Background: Alzheimer’s disease (AD) animal models have revealed neuroprotective actions of Bryostatin-1 mediated by activation of novel PKC isoforms, suppression of beta-amyloid and downregulation of inflammatory and angiogenic events, making Bryostatin-1 an attractive candidate for attenuating AD-associated neural, vascular, and cognitive disturbances. Objective: To further enhance Bryostatin-1 efficacy, nanoparticle-encapsulated Bryostatin-1 formulations were prepared. Methods: We compared nano-encapsulated and unmodified Bryostatin-1 in in vitro models of neuronal PKC-d, PKC-e isoforms, α-secretase and studied nano-encapsulated Bryostatin-1 in an AD mouse model of spatial memory (BC3-Tg (APPswe, PSEN1 dE9) 85Dbo/J mice). Results: We found that nanoencapsulated Bryostatin-1 formulations displayed activity greater or equal to that of unmodified Bryostatin-1 in PKC-δ and -ε and α-secretase activation assays. We next evaluated how treatment with a nanoencapsulated Bryostatin-1 formulation facilitated spatial learning in the Morris water maze. AD transgenic mice (6.5 to 8 months of age) were treated with nanoparticle encapsulated Bryostatin-1 formulation (1, 2.5, or 5 μg/mouse) three times the week before testing and then daily for each of the 5 days of testing. Across the acquisition phase, mice treated with nanoencapsulated Bryostatin-1 had shorter latencies, increased % time in the target zone and decreased % time in the opposite quadrant. The mice were given retention testing after a 2-week period without drug treatment. Mice treated with nanoencapsulated Bryostatin-1 had shorter latencies to find the escape platform, indicating retention of spatial memory. Conclusion: These data suggest that cognitive deficits associated with AD could be treated using highly potent nanoparticle-encapsulated formulations of Bryostatin-1.

Background: We have hypothesized that the most commonly used intravenous (propofol) and inhalational (sevoflurane) general anesthetics affect cell survival concentration and duration dependently with different potency associated with their differential potency to affect intracellular Ca⁺² homeostasis. Methods: Human neuroblastoma SH-SY5Y cells stably transfected with either wild type or M146L mutant human presenilin 1 were cultured and exposed to equipotent of propofol or sevoflurane. Cell viability, cytosolic and mitochondrial calcium were measured. Results: Sevoflurane but not propofol, at clinically relevant concentrations and durations, promoted cell survival. Prolonged exposure (24 hours) of 1% sevoflurane resulted in significant cell damage in both types of cells. Both sevoflurane and propofol had significantly higher cell response rates to the elevation of cytosolic Ca⁺² or mitochondrial Ca⁺² in the presence of extracellular calcium. With the contribution of Ca⁺² influx, sevoflurane but not equipotent 1 MAC propofol, caused a significantly greater increase in peak and overall Ca⁺² in Alzheimer’s mutation cell than in wild type cells, but significantly more increase in overall mitochondrial Ca⁺² concentrations in wild type than mutation cells. In the absence of extracellular Ca⁺² influx, sevoflurane, but not propofol, caused more significant elevations of overall mitochondrial Ca⁺² concentration in mutation cells than control cells. Conclusion: Calcium influx contributed to the general anesthetics mediated elevation of cytosolic or mitochondrial Ca⁺², which is especially true for propofol. Sevoflurane has a greater potency to either promote or inhibit cell survival than propofol, which may be associated with its ability to affect cytosolic or mitochondrial Ca⁺² concentrations.

Background: Alzheimer’s disease (AD) is the most common and irreversible neurodegenerative disorder, and amyloid peptide plays a central role in its pathogenesis. Physical training contributes as a beneficial adaptation to AD. However, these effects may be underestimated because much of the literature used fixed training prescription variables (intensity and volume) throughout the protocol. Moreover, researchers poorly understand whether chronic high-intensity interval training (HIIT) exerts similar effects on the brain tissue of individuals with AD. Objective: This study evaluated the effect of 8 minutes of HIIT with incremental overload in an AD model. Methods: Forty male Wistar rats were divided into four groups: an untrained Sham group, Sham trained group, Aβ1-42 (Alzheimer’s) untrained group, and Aβ1-42 (Alzheimer’s) trained group (n=10 rats per group). Animals underwent stereotactic surgery and received a hippocampal injection of Aβ1-42 or a saline solution. Seven days after surgery, two weeks of treadmill adaptation followed by a maximal running test (MRT) was performed. Then, animals were subjected to eight weeks of HIIT. Rats were sacrificed 24 h after the behavioral tests (open field and Morris water maze), hippocampal tissue was extracted to analyze the redox balance and BDNF/TrkB pathway, and neuritic plaques (NP) were detected by evaluating silver impregnation. Results: The AD trained group presented a physical capacity amelioration every two weeks and locomotor, learning, and memory improvements (p<0.05). These effects were accompanied by increased CAT and SOD levels, followed by decreased lipid peroxidation (p<0.05). Furthermore, increased activation of the BDNF/TrkB (p<0.05) pathway and decreased NP was observed. Conclusion: Based on these results, MRT was essential for an excellent chronic training protocol prescription and overload adjustment. Therefore, 8 minutes of HIIT daily for 8 weeks may reduce behavioral deficits by promoting a positive redox balance and increased activity of the BDNF/TrkB pathway that may contribute to NP attenuation.