Cyclic Glycine-Proline (cGP) Normalises Insulin-Like Growth Factor-1 (IGF-1) Function: Clinical Significance in the Ageing Brain and in Age-Related Neurological Conditions.

Insulin-like growth factor-1 (IGF-1) function declines with age and is associated with brain ageing and the progression of age-related neurological conditions. The reversible binding of IGF-1 to IGF binding protein (IGFBP)-3 regulates the amount of bioavailable, functional IGF-1 in circulation. Cyclic glycine-proline (cGP), a metabolite from the binding site of IGF-1, retains its affinity for IGFBP-3 and competes against IGF-1 for IGFBP-3 binding. Thus, cGP and IGFBP-3 collectively regulate the bioavailability of IGF-1. The molar ratio of cGP/IGF-1 represents the amount of bioavailable and functional IGF-1 in circulation. The cGP/IGF-1 molar ratio is low in patients with age-related conditions, including hypertension, stroke, and neurological disorders with cognitive impairment. Stroke patients with a higher cGP/IGF-1 molar ratio have more favourable clinical outcomes. The elderly with more cGP have better memory retention. An increase in the cGP/IGF-1 molar ratio with age is associated with normal cognition, whereas a decrease in this ratio with age is associated with dementia in Parkinson disease. In addition, cGP administration reduces systolic blood pressure, improves memory, and aids in stroke recovery. These clinical and experimental observations demonstrate the role of cGP in regulating IGF-1 function and its potential clinical applications in age-related brain diseases as a plasma biomarker for-and an intervention to improve-IGF-1 function.

In silico gene expression and pathway analysis of DEK in the human brain across the lifespan.

DEK, a chromatin-remodelling phosphoprotein, is associated with various functions and biological pathways in the periphery, including inflammation, oncogenesis, DNA repair, and transcriptional regulation. We recently identified an association between DEK loss and central nervous system diseases, such as Alzheimer's. To understand DEK's potential role in disease, it is critical to characterize DEK in healthy human brain to distinguish between neural DEK expression and function in healthy versus diseased states like dementia. We utilized two public databases, BrainCloud and Human Brain Transcriptome, and analysed DEK mRNA expression across the lifespan in learning and memory relevant brain regions. Since DEK loss induces phenotypes associated with brain ageing (e.g., DNA damage and apoptosis), we hypothesized that neural DEK expression may be highest during foetal development and lower in elderly individuals. In agreement with this hypothesis, DEK was most prominently expressed during foetal development in all queried forebrain areas, relative to other ages. Consistent with its roles in the periphery, pathways related to DEK in the brain were associated with cellular proliferation, DNA replication and repair, apoptosis, and inflammation. We also found novel neural development-relevant pathways (e.g., synaptic transmission, neurite outgrowth, and myelination) to be enriched from genes correlated with DEK expression. These findings suggest that DEK is important for human brain development. Overall, we highlight age-related changes in neural DEK expression across the human lifespan and illuminate novel biological pathways associated with DEK that are distinct from normal brain ageing. These findings may further our understanding of how DEK impacts brain function and disease susceptibility.

NDRG2 Expression Correlates with Neurofibrillary Tangles and Microglial Pathology in the Ageing Brain.

Astrocytes play a major role in the pathogenesis of a range of neurodegenerative diseases, including Alzheimer's disease (AD), undergoing dramatic morphological and molecular changes that can cause potentially both beneficial and detrimental effects. They comprise a heterogeneous population, requiring a panel of specific phenotype markers to identify astrocyte subtypes, changes in function and their relation to pathology. This study aimed to characterise expression of the astrocyte marker N-myc downstream regulated gene 2 (NDRG2) in the ageing brain, investigate the relationship between NDRG2 and a panel of astrocyte markers, and relate NDRG2 expression to pathology. NDRG2 specifically immunolabelled the cell body and radiating processes of astrocytes in the temporal cortex of the Cognitive Function and Ageing Study (CFAS) neuropathology cohort. Expression of NDRG2 did not correlate with other astrocyte markers, including glial fibrillary acidic protein (GFAP), excitatory amino acid transporter 2 (EAAT2) and glutamine synthetase (GS). NDRG2 showed a relationship to AT8+ neurofibrillary tangles (p = 0.001) and CD68+ microglia (p = 0.047), but not ß-amyloid plaques or astrocyte nuclear γH2AX immunoreactivity, a marker of DNA damage response. These findings provide new insight into the astrocyte response to pathology in the ageing brain, and suggest NDRG2 may be a potential target to modulate this response.

Neuronal DNA damage response-associated dysregulation of signalling pathways and cholesterol metabolism at the earliest stages of Alzheimer-type pathology.

AIMS: Oxidative damage and an associated DNA damage response (DDR) are evident in mild cognitive impairment and early Alzheimer's disease, suggesting that neuronal dysfunction resulting from oxidative DNA damage may account for some of the cognitive impairment not fully explained by Alzheimer-type pathology. METHODS: Frontal cortex (Braak stage 0-II) was obtained from the Medical Research Council's Cognitive Function and Ageing Study cohort. Neurones were isolated from eight cases (four high and four low DDR) by laser capture microdissection and changes in the transcriptome identified by microarray analysis. RESULTS: Two thousand three hundred seventy-eight genes were significantly differentially expressed (1690 up-regulated, 688 down-regulated, P < 0.001) in cases with a high neuronal DDR. Functional grouping identified dysregulation of cholesterol biosynthesis, insulin and Wnt signalling, and up-regulation of glycogen synthase kinase 3ß. Candidate genes were validated by quantitative real-time polymerase chain reaction. Cerebrospinal fluid levels of 24(S)-hydroxycholesterol associated with neuronal DDR across all Braak stages (rs = 0.30, P = 0.03). CONCLUSIONS: A persistent neuronal DDR may result in increased cholesterol biosynthesis, impaired insulin and Wnt signalling, and increased GSK3ß, thereby contributing to neuronal dysfunction independent of Alzheimer-type pathology in the ageing brain.

Neuroprotective and neurorestorative potential of propargylamine derivatives in ageing: focus on mitochondrial targets.

The mitochondrial theory of ageing proposes that accumulation of damage to mitochondrial function and DNA mutation lead to ageing of humans and animals. It has been suggested that mitochondria play dynamic roles in regulating synaptogenesis and morphological/functional responses of synaptic activity, and thus, deteriorating of mitochondrial function (e.g., deficits of the mitochondrial respiratory enzymes, reduced calcium influx, increased accumulation of mitochondrial DNA defects/apoptotic proteins and impairment of mitochondrial membrane potential) can lead to severe neuronal energy deficit, and in the long run, to modifications in neuronal synapses and neurodegeneration in the ageing brain. Hence, considering the mechanisms by which mitochondrial impairment can lead to neuronal death, the development of neuroprotective molecules that target various mitochondrial pathogenic processes can be effective in the treatment of ageing and age-related neurodegenerative diseases. This review addresses several aspects of the neuroprotective effects of propargylamine derivatives (e.g., the monoamine oxidase-B inhibitors, selegiline and rasagiline and the multifunctional drugs, ladostigil, M30 and VAR10303) in ageing with a special focus on mitochondrial molecular protective mechanisms.

Unexpected Classes of Aquaporin Channels Detected by Transcriptomic Analysis in Human Brain Are Associated with Both Patient Age and Alzheimer's Disease Status.

The altered expression of known brain Aquaporin (AQP) channels 1, 4 and 9 has been correlated with neuropathological AD progression, but possible roles of other AQP classes in neurological disease remain understudied. The levels of transcripts of all thirteen human AQP subtypes were compared in healthy and Alzheimer's disease (AD) brains by statistical analyses of microarray RNAseq expression data from the Allen Brain Atlas database. Previously unreported, AQPs 0, 6 and 10, are present in human brains at the transcript level. Three AD-affected brain regions, hippocampus (HIP), parietal cortex (PCx) and temporal cortex (TCx), were assessed in three subgroups: young controls (n = 6, aged 24-57); aged controls (n = 26, aged 78-99); and an AD cohort (n = 12, aged 79-99). A significant positive correlation (p < 10-10) was seen for AQP transcript levels as a function of the subject's age in years. Differential expressions correlated with brain region, age, and AD diagnosis, particularly between the HIP and cortical regions. Interestingly, three classes of AQPs (0, 6 and 8) upregulated in AD compared to young controls are permeable to H2O2. Of these, AQPs 0 and 8 were increased in TCx and AQP6 in HIP, suggesting a role of AQPs in AD-related oxidative stress. The outcomes here are the first to demonstrate that the expression profile of AQP channels in the human brain is more diverse than previously thought, and transcript levels are influenced by both age and AD status. Associations between reactive oxygen stress and neurodegenerative disease risk highlight AQPs 0, 6, 8 and 10 as potential therapeutic targets.

Use of 31 P magnetisation transfer magnetic resonance spectroscopy to measure ATP changes after 670 nm transcranial photobiomodulation in older adults.

Mitochondrial function declines with age, and many pathological processes in neurodegenerative diseases stem from this dysfunction when mitochondria fail to produce the necessary energy required. Photobiomodulation (PBM), long-wavelength light therapy, has been shown to rescue mitochondrial function in animal models and improve human health, but clinical uptake is limited due to uncertainty around efficacy and the mechanisms responsible. Using 31 P magnetisation transfer magnetic resonance spectroscopy (MT-MRS) we quantify, for the first time, the effects of 670 nm PBM treatment on healthy ageing human brains. We find a significant increase in the rate of ATP synthase flux in the brain after PBM in a cohort of older adults. Our study provides initial evidence of PBM therapeutic efficacy for improving mitochondrial function and restoring ATP flux with age, but recognises that wider studies are now required to confirm any resultant cognitive benefits.

Revealing genetic links of Type 2 diabetes that lead to the development of Alzheimer's disease.

Background: A factor leading to Alzheimer's Disease (AD), portrayed by peripheral insulin resistance, is Type 2 diabetes mellitus (T2D). The likelihood of T2D cases would be at boosted danger in alternating AD cases has severe social consequences. Several genes have been detected via gene expression profiling or different techniques; despite the consideration of the utility of numerous of these genes stays insufficient. Methods: This project is designed to uncover the mutual genomics motifs between AD and T2D via non-negative matrix factorization (NMF) of differentially expressed genes (DEGs) of T2D Mellitus of human cortical neurons of the neurovascular unit gene expression data. A rank factorization value is calculated by employing the combination of the NMF model with the unit invariant knee (UIK) point method. The metagenes are further determined by remarking the enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and gene ontology (GO) enrichment tools. In this study, the most highly expressed genes of metagenes are subjected to protein-protein interaction (PPI) network study to discover the most significant biomarkers of T2D Mellitus in the ageing brain. Results: We screened the most important shared genes (CDKN1A, COL22A1, EIF4A, GFAP, SLC1A1, and VIM) and essential human molecular pathways that motivate these diseases. The study aimed to validate the most significant hub genes using network-based methods which detected the corresponding relationship between AD and T2D. Conclusions: Using in silico tools, the computational pipeline has broadly examined transformed pathways and discovered promising biomarkers and drug targets. We validated the most significant hub genes using network-based methods which detected the corresponding relationship between AD and T2D. These consequences on brain cells hypothetically reserve to diabetic Alzheimer's so-called type 3 diabetes (T3D) and may offer promising methodologies for curative intrusion.

Clinically Applicable Quantitative Magnetic Resonance Morphologic Measurements of Grey Matter Changes in the Human Brain.

(1) Purpose: Quantitative magnetic resonance imaging (qMRI) measurements can be used to sensitively estimate brain morphological alterations and may support clinical diagnosis of neurodegenerative diseases (ND). We aimed to establish a normative reference database for a clinical applicable quantitative MR morphologic measurement on neurodegenerative changes in patients; (2) Methods: Healthy subjects (HCs, n = 120) with an evenly distribution between 21 to 70 years and amyotrophic lateral sclerosis (ALS) patients (n = 11, mean age = 52.45 ± 6.80 years), as an example of ND patients, underwent magnetic resonance imaging (MRI) examinations under routine diagnostic conditions. Regional cortical thickness (rCTh) in 68 regions of interest (ROIs) and subcortical grey matter volume (SGMV) in 14 ROIs were determined from all subjects by using Computational Anatomy Toolbox. Those derived from HCs were analyzed to determine age-related differences and subsequently used as reference to estimate ALS-related alterations; (3) Results: In HCs, the rCTh (in 49/68 regions) and the SGMV (in 9/14 regions) in elderly subjects were less than those in younger subjects and exhibited negative linear correlations to age (p < 0.0007 for rCTh and p < 0.004 for SGMV). In comparison to age- and sex-matched HCs, the ALS patients revealed significant decreases of rCTh in eight ROIs, majorly located in frontal and temporal lobes; (4) Conclusion: The present study proves an overall grey matter decline with normal ageing as reported previously. The provided reference may be used for detection of grey matter alterations in neurodegenerative diseases that are not apparent in standard MR scans, indicating the potential of using qMRI as an add-on diagnostic tool in a clinical setting.

MR brain image analysis in dementia: From quantitative imaging biomarkers to ageing brain models and imaging genetics.

MR brain image analysis has constantly been a hot topic research area in medical image analysis over the past two decades. In this article, it is discussed how the field developed from the construction of tools for automatic quantification of brain morphology, function, connectivity and pathology, to creating models of the ageing brain in normal ageing and disease, and tools for integrated analysis of imaging and genetic data. The current and future role of the field in improved understanding of the development of neurodegenerative disease is discussed, and its potential for aiding in early and differential diagnosis and prognosis of different types of dementia. For the latter, the use of reference imaging data and reference models derived from large clinical and population imaging studies, and the application of machine learning techniques on these reference data, are expected to play a key role.

The nuclear retention of transcription factor FOXO3a correlates with a DNA damage response and increased glutamine synthetase expression by astrocytes suggesting a neuroprotective role in the ageing brain.

The accumulation of reactive oxygen species leading to oxidative damage and cell death plays an important role in a number of neurodegenerative disorders. FOXO3a, the main isoform of FOXO transcription factors, mediates the cellular response to oxidative stress by regulating the expression of genes involved in DNA repair and glutamine metabolism, including glutamine synthetase (GS). Immunohistochemical investigation of the population-based neuropathology cohort of the Medical Research Council's Cognitive Function and Ageing Study (MRC CFAS) demonstrates that nuclear retention of FOXO3a significantly correlates with a DNA damage response and with GS expression by astrocytes. Furthermore, we show that GS expression correlates with increasing Alzheimer-type pathology in this ageing cohort. Our findings suggest that in response to oxidative stress, the nuclear retention of FOXO3a in astrocytes upregulates expression of GS as a neuroprotective mechanism. However, the activity of GS may be compromised by increasing levels of oxidative stress in the ageing brain resulting in dysfunctional enzyme activity, neuronal excitotoxic damage and cognitive impairment.