Advances in Alzheimer therapy: understanding pharmacological approaches to the disease

Although significant accomplishments have been made in research to understand, diagnose and treat Alzheimer's disease (AD) and its prequel, mild cognitive impairment, over the last two decades, a huge amount more remains to be achieved to impact this incurable, terminal disease that afflicts an estimated 26.6 million people worldwide. Increasing evidence indicates that early diagnosis will be fundamental to maximizing treatment benefits. Moreover, mechanistically-based, hypothesis-driven treatment strategies are now emerging to hopefully spearhead future therapy. The crossfertilization of ideas from multiple disciplines will prove key to optimize strategies and translate them to meaningful clinical utility, and forms the basis of the current issue focused on "Advances in Alzheimer therapy"

Lessons from a BACE1 inhibitor trial: off-site but not off base

Alzheimer's disease (AD) is characterized by formation of neuritic plaque primarily composed of a small filamentous protein called amyloid-β peptide (Aβ). The rate-limiting step in the production of Aβ is the processing of Aβ precursor protein (APP) by β-site APP-cleaving enzyme (BACE1). Hence, BACE1 activity plausibly plays a rate-limiting role in the generation of potentially toxic Aβ within brain and the development of AD, thereby making it an interesting drug target. A phase II trial of the promising LY2886721 inhibitor of BACE1 was suspended in June 2013 by Eli Lilly and Co., due to possible liver toxicity. This outcome was apparently a surprise to the study's team, particularly since BACE1 knockout mice and mice treated with the drug did not show such liver toxicity. Lilly proposed that the problem was not due to LY2886721 anti-BACE1 activity. We offer an alternative hypothesis, whereby anti-BACE1 activity may induce apparent hepatotoxicity through inhibiting BACE1's processing of β-galactoside α-2,6-sialyltransferase I (STGal6 I). In knockout mice, paralogues, such as BACE2 or cathepsin D, could partially compensate. Furthermore, the short duration of animal studies and short lifespan of study animals could mask effects that would require several decades to accumulate in humans. Inhibition of hepatic BACE1 activity in middle-aged humans would produce effects not detectable in mice. We present a testable model to explain the off-target effects of LY2886721 and highlight more broadly that so-called off-target drug effects might actually represent off-site effects that are not necessarily off-target. Consideration of this concept in forthcoming drug design, screening, and testing programs may prevent such failures in the future

In Vivo screening and discovery of novel candidate thalidomide analogs in the zebrafish embryo and chicken embryo model systems

This study was supported by a Wellcome Trust-NIH PhD Studentship to SB, WDF and NV. Grant number 098252/Z/12/Z. SB, CHC and WDF are supported by the Intramural Research Program, NCI, NIH. NHG and WL are supported by the Intramural Research Program, NIA, NIH.Peer reviewedPublisher PD

Early-life events may trigger biochemical pathways for Alzheimer's disease: the "LEARn" model

Alzheimer's disease (AD), the most common form of dementia among the elderly, manifests mostly late in adult life. However, it is presently unclear when the disease process starts and how long the pathobiochemical processes take to develop. Our goal is to address the timing and nature of triggers that lead to AD. To explain the etiology of AD, we have recently proposed a "Latent Early-life Associated Regulation" (LEARn) model, which postulates a latent expression of specific genes triggered at the developmental stage. This model integrates both the neuropathological features (e.g., amyloid-loaded plaques and tau-laden tangles) and environmental factors (e.g., diet, metal exposure, and hormones) associated with the disease. Environmental agents perturb gene regulation in a long-term fashion, beginning at early developmental stages, but these perturbations do not have pathological results until significantly later in life. The LEARn model operates through the regulatory region (promoter) of the gene and by affecting the methylation status within the promoter of specific genes

Are pulmonary fibrosis and Alzheimer's disease linked? Shared dysregulation of two miRNA species and downstream pathways accompany both disorders

As neuroscientists, we were intrigued when Huang et al. (1) reported that miR101 can attenuate pulmonary fibrosis (PF)2 through suppression of Wnt family member 5A (WNT5A). Accumulating evidence suggests that prima facie unrelated disorders in multiple fields of medicine share fundamental molecular pathways. For example, PF associates with cognitive impairment (2). It is reasonable to presume that such links would be due to hypoxia and general inflammation, but could there be a deeper connection? Both miR101 and miR27b expression levels were significantly reduced in more severe PF cases (1). These same miRNA are implicated and reduced (3, 4) in Alzheimer's disease (AD). Interestingly, while miR101 levels are reduced in late-stage AD brain samples, an miRNA associated with AD and Parkinson's disease, miR153, is not (5). Notably, miR27b regulates peroxisome proliferator–activated receptor γ (PPARγ), and PPARγ disruption is implicated in both AD and PF (3). Wnt signaling disruption is a well-known molecular feature of AD (6). That two miRNA species are both down-regulated and pathways they regulate are linked to specific pulmonary and neurological disorders is noteworthy. If we want to take a broader view of connection or divergence of progressive disorders, we also can consider that miRNAs usually have multiple mRNA targets. In addition to regulating Wnt signaling, miR101 regulates levels of the Aβ-precursor protein (APP) and, by extension, its neurotoxic processing product, Aβ (4). APP, as such, has not been directly implicated in PF, but it would not be unreasonable to propose that disruption of miR101 would impact several vital signaling and expression pathways. Disruption of a fundamental, multiorgan-wide pathway such as Wnt or PPARγ signaling could be a broad precursor to multiple disorders, with specificity to be determined by other interactions. This suggests the potential for developing a therapeutic strategy to utilize common dysregulation of specific miRNAs for disparate diseases.As neuroscientists, we were intrigued when Huang et al. (1) reported that miR101 can attenuate pulmonary fibrosis (PF)2 through suppression of Wnt family member 5A (WNT5A). Accumulating evidence suggests that prima facie unrelated disorders in multiple fields of medicine share fundamental molecular pathways. For example, PF associates with cognitive impairment (2). It is reasonable to presume that such links would be due to hypoxia and general inflammation, but could there be a deeper connection? Both miR101 and miR27b expression levels were significantly reduced in more severe PF cases (1). These same miRNA are implicated and reduced (3, 4) in Alzheimer's disease (AD). Interestingly, while miR101 levels are reduced in late-stage AD brain samples, an miRNA associated with AD and Parkinson's disease, miR153, is not (5). Notably, miR27b regulates peroxisome proliferator–activated receptor γ (PPARγ), and PPARγ disruption is implicated in both AD and PF (3). Wnt signaling disruption is a well-known molecular feature of AD (6). That two miRNA species are both down-regulated and pathways they regulate are linked to specific pulmonary and neurological disorders is noteworthy. If we want to take a broader view of connection or divergence of progressive disorders, we also can consider that miRNAs usually have multiple mRNA targets. In addition to regulating Wnt signaling, miR101 regulates levels of the Aβ-precursor protein (APP) and, by extension, its neurotoxic processing product, Aβ (4). APP, as such, has not been directly implicated in PF, but it would not be unreasonable to propose that disruption of miR101 would impact several vital signaling and expression pathways. Disruption of a fundamental, multiorgan-wide pathway such as Wnt or PPARγ signaling could be a broad precursor to multiple disorders, with specificity to be determined by other interactions. This suggests the potential for developing a therapeutic strategy to utilize common dysregulation of specific miRNAs for disparate diseases

Thalidomide Analogues Suppress Lipopolysaccharide-Induced Synthesis of TNF-α and Nitrite, an Intermediate of Nitric Oxide, in a Cellular Model of Inflammation

An unregulated neuroinflammation accompanies numerous chronic and acute neurodegenerative disorders and it is postulated that such a neuroinflammatory component likely exacerbates disease progression. A key player in brain inflammation is the microglial cell; a vital soluble factor synthesized by activated microglial cells is the key cytokine, tumor necrosis factor–alpha (TNF-α). Additionally, microglial cells release IL-1α/β, reactive oxygen species (ROS), such as superoxide (O2-) and reactive nitrogen species (RNS) like nitric oxide (NO). Nitric oxide reactive oxygen species can undergo various forms of interactions in cells whereby the synthesis of RNS / ROS intermediates are generated that can damage cell membranes. The presence of oxidative damaged cells is implicated with the abnormal cellular activity in brain or in the spinal cord, and is a classical feature of neurodegenerative disorders. To aid characterize this process, a quantitative analysis of nitrite generation was undertaken on agents developed to lower TNF-α levels in cell culture. Nitrite is a stable end product of nitric oxide metabolism and, thereby, acts as a surrogate measure of the highly unstable nitric oxide. Utilizing a RAW 264.7 cellular model of lipopolysaccharide-induced inflammation that induces high levels of TNF-α protein accompanied by a robust generation of nitrite, the properties of a series of thalidomide-based TNF-α synthesis inhibitors were evaluated to reduce the levels of both. Specific analogues of thalidomide effectively suppressed the generation of both TNF-α and nitrite at well-tolerated doses

The alpha-synuclein 5'untranslated region targeted translation blockers: anti-alpha synuclein efficacy of cardiac glycosides and Posiphen

Increased brain α-synuclein (SNCA) protein expression resulting from gene duplication and triplication can cause a familial form of Parkinson's disease (PD). Dopaminergic neurons exhibit elevated iron levels that can accelerate toxic SNCA fibril formation. Examinations of human post mortem brain have shown that while mRNA levels for SNCA in PD have been shown to be either unchanged or decreased with respect to healthy controls, higher levels of insoluble protein occurs during PD progression. We show evidence that SNCA can be regulated via the 5'untranslated region (5'UTR) of its transcript, which we modeled to fold into a unique RNA stem loop with a CAGUGN apical loop similar to that encoded in the canonical iron-responsive element (IRE) of L- and H-ferritin mRNAs. The SNCA IRE-like stem loop spans the two exons that encode its 5'UTR, whereas, by contrast, the H-ferritin 5'UTR is encoded by a single first exon. We screened a library of 720 natural products (NPs) for their capacity to inhibit SNCA 5'UTR driven luciferase expression. This screen identified several classes of NPs, including the plant cardiac glycosides, mycophenolic acid (an immunosuppressant and Fe chelator), and, additionally, posiphen was identified to repress SNCA 5'UTR conferred translation. Western blotting confirmed that Posiphen and the cardiac glycoside, strophanthidine, selectively blocked SNCA expression (~1 μM IC(50)) in neural cells. For Posiphen this inhibition was accelerated in the presence of iron, thus providing a known APP-directed lead with potential for use as a SNCA blocker for PD therapy. These are candidate drugs with the potential to limit toxic SNCA expression in the brains of PD patients and animal models in vivo