Current Alzheimer Research - Volume 14, Issue 11, 2017

Background: Microglial activation is a hallmark of neuroinflammation, seen in most acute and chronic neuropsychiatric conditions. With growing knowledge about microglia functions in surveying the brain for alterations, microglial activation is increasingly discussed in the context of disease progression and pathogenesis of Alzheimer's disease (AD). Underlying molecular mechanisms, however, remain largely unclear. While proper microglial function is essentially required for its scavenging duties, local activation of the brain’s innate immune cells also brings about many less advantageous changes, such as reactive oxygen species (ROS) production, secretion of proinflammatory cytokines or degradation of neuroprotective retinoids, and may thus unnecessarily put surrounding healthy neurons in danger. In view of this dilemma, it is little surprising that both, AD vaccination trials, and also immunosuppressive strategies have consistently failed in AD patients. Nevertheless, epidemiological evidence has suggested a protective effect for anti-inflammatory agents, supporting the hypothesis that key processes involved in the pathogenesis of AD may take place rather early in the time course of the disorder, likely long before memory impairment becomes clinically evident. Activation of microglia results in a severely altered microenvironment. This is not only caused by the plethora of secreted cytokines, chemokines or ROS, but may also involve increased turnover of neuroprotective endogenous substances such as retinoic acid (RA), as recently shown in vitro. Results: We discuss findings linking microglial activation and AD and speculate that microglial malfunction, which brings about changes in local RA concentrations in vitro, may underlie AD pathogenesis and precede or facilitate the onset of AD. Thus, chronic, “innate neuroinflammation” may provide a valuable target for preventive and therapeutic strategies.

Objective: The dramatic increase in the population with dementia expected in the next decades is accompanied by the establishment of novel and innovated methods that will offer accurate and efficient detection of the disease in its early stages. While Alzheimer's disease is the most common cause of dementia, by the time it is typically diagnosed, substantial neuronal loss and neuropathological lesions can damage many brain regions. The aim of this study is to investigate the main risk factors that affect and increase Alzheimer's disease progression over time even in cases with no significant memory impairment present. Several potential markers are discussed such as oxidative stress, metal ions, vascular disorders, protein dysfunctions and alterations in the mitochondrial populations. Conclusion: A multiparametric model of Alzheimer's biomarkers is presented according to the latest classification of the disease.

Background: The vascular endothelial growth factor (VEGF) is a neuroprotective cytokine that promotes neurogenesis and angiogenesis in the brain. In animal models, it has been shown that environmental enrichment and exercise, two non-pharmacological interventions that are beneficial decreasing the progression of Alzheimer disease (AD) and depressive-like behavior, enhance hippocampal VEGF expression and neurogenesis. Furthermore, the stimulation of VEGF expression promotes neurotransmission and synaptic plasticity processes such as neurogenesis. It is thought that these VEGF actions in the brain, may underly its beneficial therapeutic effects against psychiatric and other neurological conditions. Conclusion: In this review, evidence linking VEGF deficit with the development of AD as well as the potential role of VEGF signaling as a therapeutic target for cotinine and other interventions in neurodegenerative conditions are discussed.

Background: Alzheimer's disease (AD), a cognitive dysfunction/dementia state amongst the elders is characterized by irreversible neurodegeneration due to varied pathophysiology. Up till now, anti-AD drugs having different pharmacology have been developed and used in clinic. Yet, these medications are not curative and only lowering the AD associated symptoms. Improvement in treatment outcome required drug targeting across the blood-brain barrier (BBB) to the central nervous system (CNS) in optimal therapeutic concentration. Nanotechnology based diagnostic tools, drug carriers and theranostics offer highly sensitive molecular detection, effective drug targeting and their combination. Over the past decade, significant works have been done in this area and we have seen very remarkable outocome in AD therapy. Various nanoparticles from organic and inorganic nanomaterial category have successfully been investigated against AD. Conclusion: This paper discussed the role of nanoparticles in early detection of AD, effective drug targeting to brain and theranostic (diagnosis and therapy) approaches in AD's management.

Background: Alzheimer disease (AD) typically affects behavior, memory and thinking. The change in brain have been reported to begin approx. 10-20 years before the appearance of actual symptoms and diagnosis of AD. An early stage diagnosis and treatment of this lethal disease is the prime challenge, which is mainly halted by the lack of validated biomarkers. Method: Recent nanotechnological advancements have the potential to offer large scale effective diagnostic and therapeutic options. Targeted drug (e.g. Rivastigmine) delivery with the help of nanoparticles (NPs) in the range of 1-100 nm diameters can effectively cross the blood brain barrier with minimized side effects. Moreover, biocompatible nanomaterials with increased magnetic and optical properties can act as excellent alternative agents for an early diagnosis. With the high volume of research coming in support of the effective usage of NP based drug delivery in critical environment of CNS, it is quite likely that this approach can end up providing remarkable breakthroughs in early stage diagnosis and therapy of AD. Conclusion: In the current review, we have presented a comprehensive outlook on the current challenges in diagnosis and therapy of AD, with an emphasis on the effective options provided by biocompatible NPs as imaging contrast agents and drug carriers.

Background: Alzheimer's disease (AD) is the most common and well-studied neurodegenerative disease (ND). Biological pathways, pathophysiology and genetics of AD show commonalities with other NDs viz. Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Prion disease and Dentatorubral-pallidoluysian atrophy (DRPLA). Many of the NDs, sharing the common features and molecular mechanisms suggest that pathology may be directly comparable and be implicated in disease prevention and development of highly effective therapies. Method: In this review, a brief description of pathophysiology, clinical symptoms and available treatment of various NDs have been explored with special emphasis on AD. Commonalities in these fatal NDs provide support for therapeutic advancements and enhance the understanding of disease manifestation. Conclusion: The studies concentrating on the commonalities in biological pathways, cellular mechanisms and genetics may provide the scope to researchers to identify few novel common target(s) for disease prevention and development of effective common drugs for multi-neurodegenerative diseases.

Background: Alzheimer's disease is a neurodegenerative disorder which generally affects people who are more than 60 years of age. The disease is clinically characterised by dementia, loss of cognitive functions and massive neurodegeneration. The presence of neurofibrilary tangles and amyloid plaques in the hippocampal region of the brain are the hallmarks of the disease. Current therapeutic approaches for the treatment of Alzheimer's disease are symptomatic and disease modifying, none of which provide any permanent solution or cure for the disease. Dysregulation of miRNAs is one of the major causes of neurodegeneration. Conclusion: In the present review, the roles of different miRNAs such as miR-9, miR-107, miR-29, miR-34, miR-181, miR-106, miR-146a, miR132, miR124a, miR153 has been discussed in detail in the pathogenesis of various neurodegenerative diseases with special focus on AD. The probability of miRNAs as an alternative and more sensitive approach for detection and management of the AD has also been discussed.

Background: Previous studies have suggested that the expression of Aβ and clusterin is positively correlated. However, the causal relationship between Aβ and clusterin has not been exactly clarified. Methods: In this study, primary hippocampal neurons were treated with Aβ42; clusterin mRNA and protein expression was assessed. Furthermore, we evaluated Aβ and clusterin protein expression in the brains of APP/PSEN1 mice, as well as serum clusterin concentration. Results: We observed here that the exposure of primary hippocampal neurons to Aβ42 induced an overexpression of intracellular clusterin, but the level of clusterin in supernatants was not changed. Moreover, in APP/PSEN1 mice, there was a significant increase in intracellular clusterin in cortex and hippocampus, compared to age-matched WT mice, while serum clusterin level in APP/PSEN1 mice and in WT mice has no significant difference. Conclusion: Aβ42 upregulated intracellular clusterin, but secretory clusterin did not change. These findings reveal that clusterin is upregulated by Aβ and is responsive to AD pathology, although plasma clusterin concentration is not evidenced to be a stand-alone biomarker for AD.

Background: Alzheimer's disease (AD) is accompanied by a neuroinflammation triggering chemoattractant signals towards peripheral blood mononuclear cells (PBMCs), which in turn could reduce amyloid plaques after transmigration through the blood brain barrier (BBB). But the chemotactic environment remains unclear. Objective: To analyze five chemokines known to be involved in AD in three different cellular models to better understand the cellular and molecular interactions in the BBB. Method: Chemokines (CCL-2, 4 and 5, CXCL10 and CX3CL1) were measured in isolated cells, a BBB model without PBMCs (H4 and hCMEC/D3 cells, a neuroglioma and human endothelial cells, respectively) and in a complete BBB model with PBMCs from AD patients at a moderate stage. In one set of experiments, H4 cells were treated with Aβ42. Results: CCL2 and CCL5 significantly increased in hCMEC/D3 and H4 cells in the complete BBB model. In turn, the rate of CCL2 increased in PBMCs whereas for CCL5, it decreased. CXCL10 increased in all cellular actors in the complete BBB model, compared to isolated cells. For CCL4, PBMCs induced a robust increase in H4 and hCMEC/D3. In turn, the level of CCL4 decreased in PBMCs. Furthermore, PBMCs triggered a significant increase in CX3CL1 in hCMEC/D3. Surprisingly, no effect of Aβ42 was observed in the complete BBB model. Conclusion: These findings highlight the interest of a BBB model in order to explore chemokine production. For the first time, results showed that PBMCs from patients with AD can control the production of CCL4 and CXCL10 in a human BBB model.

Objective: Generation and accumulation of the amyloid-β (Aβ) peptide after proteolytic processing of the full length amyloid precursor protein (FL-APP) by β-secretase (β-site APP cleaving enzyme or BACE1) and γ-secretase are the main causal factors of Alzheimer's disease (AD). Thus, inhibition of BACE1, a rate-limiting enzyme in the production of Aβ, is an attractive therapeutic approach for the treatment of AD. Recent studies suggest that salvianolic acid B (Sal B) is isolated from the radix of Salvia miltiorrhiza Bunge, a Chinese herbal medicine commonly used for the treatment of cardiovascular, cerebrovascular and liver diseases in China. Method: In this study, we discovered that Sal B acted as a BACE1 modulator and reduced the level of secreted Aβ in two different Swedish APP (SwedAPP) mutant cell lines. Using N2a-mouse and H4- human neuroglioma cell lines expressing SwedAPP, it was demonstrated that Sal B significantly and dose-dependently decreased the generation of extracellular Aβ, soluble APPβ (by-product of APP cleaved by BACE1), and intracellular C-terminal fragment β from APP without influencing α-secretase and γ-secretase activity and the levels of FL-APP. In addition, using protein-docking, we determined the potential conformation of Sal B on BACE1 docking and revealed the interactions of Sal B with the BACE1 catalytic center. Results: The docking provides a feasible explanation for the experimental results, especially in terms of the molecular basis of Sal B's action. Our results indicate that Sal B is a BACE1 inhibitor and, as such, is a promising candidate for the treatment of AD

Background: As a risk factor for Alzheimer's disease (AD), type 2 diabetes mellitus (T2DM) itself causes cognitive impairment and has higher prevalence of mild cognitive impairment (MCI). Objective: The aim of this study was to explore the cognition especially the episodic memory difference, the DMN functional connectivity and DMN-related white matter integrity in patients with both T2DM and amnestic MCI (T2DM-MCI) as compared to patients with T2DM only. Methods: Focusing especially on T2DM population, we investigated the default mode network (DMN) through resting-state functional magnetic resonance imaging among 22 elderly T2DM-MCI patients and 24 elderly T2DM patients. Including primarily the bilateral cingulum, hippocampus and uncinate fasciculus, these DMN white matter fibers were also closely associated with episodic memory and the integrity of them was also investigated using diffusion tensor imaging in 19 elderly T2DM-MCI patients and 23 elderly T2DM patients. Results: Compared with the patients with T2DM, the T2DM-MCI patients performed worse in several areas of cognition besides episodic memory, and showed stronger DMN functional connectivity in the left precuneus and weaker functional connectivity in the left calcarine, as well as decreased integrity of the left cingulate bundle and bilateral uncinate fasciculus. Furthermore, a correlation analysis indicated that higher left calcarine connectivity was associated with better episodic memory performance among the overall group. Conclusion: Our results demonstrated that T2DM patients with comorbid amnestic MCI had abnormal functional connectivity patterns and decreased white matter integrity, which could potentially serve as AD or AD risk biomarkers for early detection of those elderly individuals with T2DM.