Alzheimer's Disease (AD), the most prevalent neurodegenerative disease of aging, affects one in eight older Americans. Nearly all drug treatments tested for AD today have failed to show any efficacy. ...There is a great need for therapies to prevent and/or slow the progression of AD. The major challenge in AD drug development is lack of clarity about the mechanisms underlying AD pathogenesis and pathophysiology. Several studies support the notion that AD is a multifactorial disease. While there is abundant evidence that amyloid plays a role in AD pathogenesis, other mechanisms have been implicated in AD such as tangle formation and spread, dysregulated protein degradation pathways, neuroinflammation, and loss of support by neurotrophic factors. Therefore, current paradigms of AD drug design have been shifted from single target approach (primarily amyloid-centric) to developing drugs targeted at multiple disease aspects, and from treating AD at later stages of disease progression to focusing on preventive strategies at early stages of disease development. Here, we summarize current strategies and new trends of AD drug development, including pre-clinical and clinical trials that target different aspects of disease (mechanism-based versus non-mechanism based, e.g. symptomatic treatments, lifestyle modifications and risk factor management).
Our recent findings link the apolipoprotein E4 (ApoE4)-specific changes in brain phosphoinositol biphosphate (PIP
) homeostasis to the susceptibility of developing Alzheimer's Disease (AD). In the ...present study, we have identified miR-195 as a top micro-RNA candidate involved in the ApoE/PIP
pathway using miRNA profiles in human ROSMAP datasets and mouse microarray studies. Further validation studies have demonstrated that levels of miR-195 are significantly lower in human brain tissue of ApoE4
patients with clinical diagnosis of mild cognitive impairment (MCI) or early AD when compared to ApoE4
subjects. In addition, brain miR-195 levels are reduced along with disease progression from normal aging to early AD, and cerebrospinal fluid (CSF) miR-195 levels of MCI subjects are positively correlated with cognitive performances as measured by mini-mental status examination (MMSE) and negatively correlated with CSF tau levels, suggesting the involvement of miR-195 in early development of AD with a potential impact on cognition. Similar differences in miR-195 levels are seen in ApoE4
mouse hippocampal brain tissue and cultured neurons when compared to ApoE3
counterparts. Over-expressing miR-195 reduces expression levels of its top predicted target synaptojanin 1 (synj1), a brain PIP
-degrading enzyme. Furthermore, elevating miR-195 ameliorates cognitive deficits, amyloid plaque burden, and tau hyper-phosphorylation in ApoE4
mice. In addition, elevating miR-195 rescues AD-related lysosomal defects in inducible pluripotent stem cells (iPSCs)-derived brain cells of ApoE4
AD subjects while inhibiting miR-195 exacerbates these phenotypes. Together, our data uncover a novel regulatory mechanism of miR-195 targeted at ApoE4-associated brain PIP
dyshomeostasis, cognitive deficits, and AD pathology.
To identify the molecular mechanisms and novel therapeutic targets of late-onset Alzheimer’s Disease (LOAD), we performed an integrative network analysis of multi-omics profiling of four cortical ...areas across 364 donors with varying cognitive and neuropathological phenotypes. Our analyses revealed thousands of molecular changes and uncovered neuronal gene subnetworks as the most dysregulated in LOAD. ATP6V1A was identified as a key regulator of a top-ranked neuronal subnetwork, and its role in disease-related processes was evaluated through CRISPR-based manipulation in human induced pluripotent stem cell-derived neurons and RNAi-based knockdown in Drosophila models. Neuronal impairment and neurodegeneration caused by ATP6V1A deficit were improved by a repositioned compound, NCH-51. This study provides not only a global landscape but also detailed signaling circuits of complex molecular interactions in key brain regions affected by LOAD, and the resulting network models will serve as a blueprint for developing next-generation therapeutic agents against LOAD.
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•Development of gene network models of four cortical areas affected by LOAD•Identification of region-specific molecular changes and gene subnetworks in LOAD•ATP6V1A is a top key regulator of a neuronal subnetwork most disrupted in LOAD•NCH-51 normalizes neuronal impairment and neurodegeneration caused by ATP6V1A deficit
Employing an integrative network biology approach, Wang et al. identify critical gene subnetworks associated with late-onset Alzheimer’s disease (LOAD) and predict ATP6V1A as a key regulator of a neuron-specific subnetwork most affected by LOAD. ATP6V1A deficit causes neuronal impairment and neurodegeneration, which are normalized by a predicted compound, NCH-51.
The preparation of CuCo
2
O
4
material with a suitable phase structure and grain size can improve its lithium storage performance. In this paper, CuCo
2
O
4
hexagonal nanocrystal were successfully ...obtained by molten salt modified urea combustion method. Compared with the traditional high temperature solid state methods such as combustion method, rheological phase method and precipitation method, this method maintains the advantage of simple operation, and the particle size of the sample is smaller. The effect of heat treatment temperature on the lithium storage performance of CuCo
2
O
4
was also studied systematically in this paper. The result shows that 800 ℃ is the best heat treatment temperature for CuCo
2
O
4
, and the sample synthesized by the molten salt urea combustion method exhibited the best electrochemical properties with a specific capacity of 705 mA h g
-1
after 100 cycles under a constant current of 200 mA g
-1
in the voltage range of 0.01-3 V. Therefore, a new strategy of high temperature solid state preparation has been developed in this paper, and the CuCo
2
O
4
synthesized by this method is a promising anode material for lithium ion battery application.
The apolipoprotein E4 (ApoE4) allele is the strongest genetic risk factor for developing sporadic Alzheimer’s disease (AD). However, the mechanisms underlying the pathogenic nature of ApoE4 are not ...well understood. In this study, we have found that ApoE proteins are critical determinants of brain phospholipid homeostasis and that the ApoE4 isoform is dysfunctional in this process. We have found that the levels of phosphoinositol biphosphate (PIP₂) are reduced in postmortem human brain tissues of ApoE4 carriers, in the brains of ApoE4 knock-in (KI) mice, and in primary neurons expressing ApoE4 alleles compared with those levels in ApoE3 counterparts. These changes are secondary to increased expression of a PIP₂-degrading enzyme, the phosphoinositol phosphatase synaptojanin 1 (synj1), in ApoE4 carriers. Genetic reduction of synj1 in ApoE4 KI mouse models restores PIP₂ levels and, more important, rescues AD-related cognitive deficits in these mice. Further studies indicate that ApoE4 behaves similar to ApoE null conditions, which fails to degrade synj1 mRNA efficiently, unlike ApoE3 does. These data suggest a loss of function of ApoE4 genotype. Together, our data uncover a previously unidentified mechanism that links ApoE4-induced phospholipid changes to the pathogenic nature of ApoE4 in AD.
Alzheimer's disease (AD) is the most common neurodegenerative disease in the United States (US). Animal models, specifically mouse models have been developed to better elucidate disease mechanisms ...and test therapeutic strategies for AD. A large portion of effort in the field was focused on developing transgenic (Tg) mouse models through over-expression of genetic mutations associated with familial AD (FAD) patients. Newer generations of mouse models through knock-in (KI)/knock-out (KO) or CRISPR gene editing technologies, have been developed for both familial and sporadic AD risk genes with the hope to more accurately model proteinopathies without over-expression of human AD genes in mouse brains. In this review, we summarized the phenotypes of a few commonly used as well as newly developed mouse models in translational research laboratories including the presence or absence of key pathological features of AD such as amyloid and tau pathology, synaptic and neuronal degeneration as well as cognitive and behavior deficits. In addition, advantages and limitations of these AD mouse models have been elaborated along with discussions of any sex-specific features. More importantly, the omics data from available AD mouse models have been analyzed to categorize molecular signatures of each model reminiscent of human AD brain changes, with the hope to guide future selection of most suitable models for specific research questions to be addressed in the AD field.
Abstract
Synaptojanin1 (synj1) is a phosphoinositide phosphatase with dual SAC1 and 5′-phosphatase enzymatic activities in regulating phospholipid signaling. The brain-enriched isoform has been shown ...to participate in synaptic vesicle (SV) recycling. More recently, recessive human mutations were identified in the two phosphatase domains of SYNJ1, including R258Q, R459P and R839C, which are linked to rare forms of early-onset Parkinsonism. We now demonstrate that Synj1 heterozygous deletion (Synj1+/−), which is associated with an impaired 5′-phosphatase activity, also leads to Parkinson’s disease (PD)-like pathologies in mice. We report that male Synj1+/− mice display age-dependent motor function abnormalities as well as alpha-synuclein accumulation, impaired autophagy and dopaminergic terminal degeneration. Synj1+/− mice contain elevated 5′-phosphatase substrate, PI(4,5)P2, particularly in the midbrain neurons. Moreover, pharmacological elevation of membrane PI(4,5)P2 in cultured neurons impairs SV endocytosis, specifically in midbrain neurons, and further exacerbates SV trafficking defects in Synj1+/− midbrain neurons. We demonstrate down-regulation of SYNJ1 transcript in a subset of sporadic PD brains, implicating a potential role of Synj1 deficiency in the decline of dopaminergic function during aging.
Common genetic variants in more than forty loci modulate risk for Alzheimer’s disease (AD). AD risk alleles are enriched within enhancers active in myeloid cells, suggesting that microglia, the ...brain-resident macrophages, may play a key role in the etiology of AD. A major genetic risk factor for AD is Apolipoprotein E (APOE) genotype, with the ε4/ε4 (E4) genotype increasing risk for AD by approximately 15 fold compared to the most common ε3/ε3 (E3) genotype. However, the impact of APOE genotype on microglial function has not been thoroughly investigated. To address this, we cultured primary microglia from mice in which both alleles of the mouse Apoe gene have been humanized to encode either human APOE ε3 or APOE ε4. Relative to E3 microglia, E4 microglia exhibit altered morphology, increased endolysosomal mass, increased cytokine/chemokine production, and increased lipid and lipid droplet accumulation at baseline. These changes were accompanied by decreased translation and increased phosphorylation of eIF2ɑ and eIF2ɑ-kinases that participate in the integrated stress response, suggesting that E4 genotype leads to elevated levels of cellular stress in microglia relative to E3 genotype. Using live-cell imaging and flow cytometry, we also show that E4 microglia exhibited increased phagocytic uptake of myelin and other substrates compared to E3 microglia. While transcriptomic profiling of myelin-challenged microglia revealed a largely overlapping response profile across genotypes, differential enrichment of genes in interferon signaling, extracellular matrix and translation-related pathways was identified in E4 versus E3 microglia both at baseline and following myelin challenge. Together, our results suggest E4 genotype confers several important functional alterations to microglia even prior to myelin challenge, providing insight into the molecular and cellular mechanisms by which APOE4 may increase risk for AD.
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•APOE4 vs APOE3 (E4/E3) mouse microglia in vitro (MG) show reactive morphology and cytokine profile.•E4/E3 MG show increased phagocytic uptake and impaired degradation of myelin.•E4/E3 MG show increased neutral lipid and endolysosomal content.•E4/E3 MG show increased interferon and eIF2 signaling, and repressed translation.•Modulation of eIF2 signaling and cell stress in MG may be a therapeutic lead for AD.
Spinal cord injury (SCI) is a devastating, life-altering, neurological event that affects ∼300,000 individuals in the United States. Currently, there are no effective treatments to reverse the ...neurological impairments caused by the lesion. Until a cure is available, there is an urgent need for strategies that can either spare injured neurons or promote neuroplasticity and functional recovery. Genetic links to outcomes after SCI may provide insights into the pathological mechanisms, and possible new avenues for drug development. In the present review, we discuss the current knowledge linking apolipoprotein E genotypes with better or worse functional outcomes after an SCI, and the possible molecular mechanisms that may contribute to this association.
Nested variant of urothelial carcinoma (NVUC) is an uncommon variant with minimally atypical cytology, which may overlap with benign urothelial lesions such as von Brunn nests, cystitis cystica, ...cystitis glandularis, and nephrogenic adenoma. Because of the tumor's deceptively bland appearance, these cancers can potentially be misdiagnosed as benign lesions, leading in some cases to a significant delay in correct diagnosis and appropriate treatment. Prior studies suggest that Ki67 and p53 are useful markers in distinguishing NVUC from benign lesions. However, the overlap in the rates of immunoreactivity has prevented pathologists from using these markers as reliable adjunct markers in differentiating NVUC from mimickers. In addition, large nested variant urothelial carcinoma (LNVUC), a relatively new entity, shares features of both the NVUC and papillary urothelial carcinomas with an inverted growth pattern. They also mimic benign lesions, such as proliferation of von Brunn nests and inverted urothelial papilloma. With the recent demonstration of a strong association of TERT promoter mutations and urothelial carcinoma, we hypothesized that TERT promoter mutations would be a useful marker to distinguish NVUC and LNVUC from other benign urothelial lesions. We have therefore sequenced the TERT promoter region of 20 cases of NVUC, 10 cases of LNVUC, 5 cases of von Brunn nests, 3 cases of cystitis cystica, 3 cases of cystitis glandularis, and 3 cases of nephrogenic adenoma. We found that 17 of 20 cases of NVUC and 8 of 10 cases of LNVUC had TERT promoter mutation: C228T; no mutation was found in any of the benign mimickers (0/14). This result strongly suggests that TERT promoter mutation is a useful adjunct biomarker to distinguish NVUC and LNVUC from benign mimickers.
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