Vascular cognitive impairment and dementia Gorelick, Philip B.; Counts, Scott E.; Nyenhuis, David
Biochimica et biophysica acta,
05/2016, Volume:
1862, Issue:
5
Journal Article
Peer reviewed
Open access
Vascular contributions to cognitive impairment are receiving heightened attention as potentially modifiable factors for dementias of later life. These factors have now been linked not only to ...vascular cognitive disorders but also Alzheimer's disease. In this chapter we review 3 related topics that address vascular contributions to cognitive impairment: 1. vascular pathogenesis and mechanisms; 2. neuropsychological and neuroimaging phenotypic manifestations of cerebrovascular disease; and 3. prospects for prevention of cognitive impairment of later life based on cardiovascular and stroke risk modification. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.
•Age-related cerebrovascular factors and pathological events precipitate VCID.•Neuropsychological and neuroimaging manifestations of cerebrovascular disorders•Current thinking on CVD and VCID risk factors and prevention•A variety of animal models have been developed to replicate vascular pathology.•Neuroimaging and neuropsychology advances provide more complete understanding of VCI.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mitochondrial perturbations such as oxidative stress, increased fission/fusion dysfunction, and mitophagy are consistent features of Alzheimer's disease (AD), yet the mechanisms that initiate these ...perturbations are unclear. One potential source for mitochondrial defects could be an imbalance in mitochondrial proteostasis. In this regard, studies indicate that a specialized mitochondrial unfolded protein response (mtUPR) is activated upon the aberrant accumulation of damaged or unfolded proteins in the mitochondrial matrix, resulting in the up-regulation of key genes involved in mitochondrial stabilization. To test whether mtUPR activation occurs in AD, we performed real-time quantitative PCR on postmortem frontal cortex samples from subjects classified as sporadic AD, familial AD linked to presenilin-1 mutations, or cognitively intact controls. Compared to controls, sporadic AD subjects exhibited a significant ~40-60% increase in expression levels of select genes activated by the mtUPR, including mitochondrial chaperones dnaja3, hspd1, and hspe1, mitochondrial proteases clpp and yme1l1, and txn2, a mitochondrial-specific oxidoreductase. Furthermore, levels of all six mtUPR genes were significantly up-regulated by ~70-90% in familial AD compared to controls, and these expression levels were significantly higher compared to sporadic AD. The increase in hspd1 (Hsp60) was validated by western blotting. These data support the concept that both sporadic and familial AD are characterized by mtUPR gene activation. Understanding the physiological consequences of this response may provide subcellular mechanistic clues to selective neuronal vulnerability or endogenous compensatory mechanisms during the progression of AD.
The recent failures of potential disease-modifying drugs for Alzheimer’s disease (AD) may reflect the fact that the enrolled participants in clinical trials are already too advanced to derive a ...clinical benefit. Thus, well-validated biomarkers for the early detection and accurate diagnosis of the preclinical stages of AD will be crucial for therapeutic advancement. The combinatorial use of biomarkers derived from biological fluids, such as cerebrospinal fluid (CSF), with advanced molecular imaging and neuropsychological testing may eventually achieve the diagnostic sensitivity and specificity necessary to identify people in the earliest stages of the disease when drug modification is most likely possible. In this regard, positive amyloid or tau tracer retention on positron emission tomography imaging, low CSF concentrations of the amyloid-β 1-42 peptide, high CSF concentrations in total tau and phospho-tau, mesial temporal lobe atrophy on magnetic resonance imaging, and temporoparietal/precuneus hypometabolism or hypoperfusion on 18F-fluorodeoxyglucose positron emission tomography have all emerged as biomarkers for the progression to AD. However, the ultimate AD biomarker panel will likely involve the inclusion of novel CSF and blood biomarkers more precisely associated with confirmed pathophysiologic mechanisms to improve its reliability for detecting preclinical AD. This review highlights advancements in biological fluid and imaging biomarkers that are moving the field towards achieving the goal of a preclinical detection of AD.
Alzheimer's disease is a common and devastating disease characterized by aggregation of the amyloid-β peptide. However, we know relatively little about the underlying molecular mechanisms or how to ...treat patients with Alzheimer's disease. Here we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in diseases involving amyloid-β proteotoxicity in human, mouse and Caenorhabditis elegans that involves the mitochondrial unfolded protein response and mitophagy pathways. Using a worm model of amyloid-β proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed that the induction of this mitochondrial stress response was essential for the maintenance of mitochondrial proteostasis and health. Notably, increasing mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases the fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms and in transgenic mouse models of Alzheimer's disease. Our data support the relevance of enhancing mitochondrial proteostasis to delay amyloid-β proteotoxic diseases, such as Alzheimer's disease.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
J. Neurochem. (2010) 113, 649–660.
Degeneration of locus coeruleus (LC) noradrenergic forebrain projection neurons is an early feature of Alzheimer’s disease. The physiological consequences of this ...phenomenon are unclear, but observations correlating LC neuron loss with increased Alzheimer’s disease pathology in LC projection sites suggest that noradrenaline (NA) is neuroprotective. To investigate this hypothesis, we determined that NA protected both hNT human neuronal cultures and rat primary hippocampal neurons from amyloid‐β (Aβ1–42 and Aβ25–35) toxicity. The noradrenergic co‐transmitter galanin was also effective at preventing Aβ‐induced cell death. NA inhibited Aβ25–35‐mediated increases in intracellular reactive oxygen species, mitochondrial membrane depolarization, and caspase activation in hNT neurons. NA exerted its neuroprotective effects in these cells by stimulating canonical β1 and β2 adrenergic receptor signaling pathways involving the activation of cAMP response element binding protein and the induction of endogenous nerve growth factor (NGF) and brain‐derived neurotrophic factor (BDNF). Treatment with functional blocking antibodies for either NGF or BDNF blocked NA’s protective actions against Aβ1–42 and Aβ25–35 toxicity in primary hippocampal and hNT neurons, respectively. Taken together, these data suggest that the neuroprotective effects of noradrenergic LC afferents result from stimulating neurotrophic NGF and BDNF autocrine or paracrine loops via β adrenoceptor activation of the cAMP response element binding protein pathway.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Clinical neuropathologic studies suggest that the selective vulnerability of hippocampal CA1 pyramidal projection neurons plays a key role in the onset of cognitive impairment during the early phases ...of Alzheimer's disease (AD). Disruption of this neuronal population likely affects hippocampal pre- and postsynaptic efficacy underlying episodic memory circuits. Therefore, identifying perturbations in the expression of synaptic gene products within CA1 neurons prior to frank AD is crucial for the development of disease modifying therapies. Here we used custom-designed microarrays to examine progressive alterations in synaptic gene expression within CA1 neurons in cases harvested from the Rush Religious Orders Study who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI, a putative prodromal AD stage), or mild/moderate AD. Quantitative analysis revealed that 21 out of 28 different transcripts encoding regulators of synaptic function were significantly downregulated (1.4–1.8 fold) in CA1 neurons in MCI and AD compared to NCI, whereas synaptic transcript levels were not significantly different between MCI and AD. The downregulated transcripts encoded regulators of presynaptic vesicle trafficking, including synaptophysin and synaptogyrin, regulators of vesicle docking and fusion/release, such as synaptotagmin and syntaxin 1, and regulators of glutamatergic postsynaptic function, including PSD-95 and synaptopodin. Clinical pathologic correlation analysis revealed that downregulation of these synaptic markers was strongly associated with poorer antemortem cognitive status and postmortem AD pathological criteria such as Braak stage, NIA-Reagan, and CERAD diagnosis. In contrast to the widespread loss of synaptic gene expression observed in CA1 neurons in MCI, transcripts encoding β-amyloid precursor protein (APP), APP family members, and regulators of APP metabolism were not differentially regulated in CA1 neurons across the clinical diagnostic groups. Taken together, these data suggest that CA1 synaptic gene dysregulation occurs early in the cascade of pathogenic molecular events prior to the onset of AD, which may form the basis for novel pharmacological treatment approaches for this dementing disorder.
This article is part of a Special Issue entitled ‘Neurodegenerative Disorders’.
•Hippocampal CA1 neurons display widespread synaptic gene downregulation in MCI and AD.•Genes encoding APP and APP family members were unaffected in MCI and AD.•Synaptic mRNA levels correlate with poorer cognition and increased AD pathology.•CA1 synaptic dysregulation is a very early pathogenic event in AD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK
Unscheduled cell cycle reentry of postmitotic neurons has been described in cases of mild cognitive impairment (MCI) and Alzheimer's disease (AD) and may form a basis for selective neuronal ...vulnerability during disease progression. In this regard, the multifunctional protein regulator of cell cycle (RGCC) has been implicated in driving G1/S and G2/M phase transitions through its interactions with cdc/cyclin-dependent kinase 1 (cdk1) and is induced by p53, which mediates apoptosis in neurons. We tested whether RGCC levels were dysregulated in frontal cortex samples obtained postmortem from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), MCI, or AD. RGCC mRNA and protein levels were upregulated by ~50%-60% in MCI and AD compared to NCI, and RGCC protein levels were associated with poorer antemortem global cognitive performance in the subjects examined. To test whether RGCC might regulate neuronal cell cycle reentry and apoptosis, we differentiated neuronotypic PC12 cultures with nerve growth factor (NGF) followed by NGF withdrawal to induce abortive cell cycle activation and cell death. Experimental reduction of RGCC levels increased cell survival and reduced levels of the cdk1 target cyclin B1. RGCC may be a candidate cell cycle target for neuroprotection during the onset of AD.
Abstract
Vascular dementia (VaD) is cognitive decline linked to reduced cerebral blood perfusion, yet there are few therapeutic options to protect cognitive function following cerebrovascular ...accidents. The purpose of this study was to profile gene expression changes unique to VaD to identify and characterize disease relevant changes that could offer clues for future therapeutic direction. Microarray-based profiling and validation studies of postmortem frontal cortex samples from VaD, Alzheimer disease, and age-matched control subjects revealed that the oxytocin receptor (OXTR) was strongly and differentially upregulated in VaD. Further characterization in fixed tissue from the same cases showed that OXTR upregulation occurs de novo around and within microinfarcts in peri-infarct reactive astrocytes as well as within vascular profiles, likely on microvascular endothelial cells. These results indicate that increased OXTR expression in peri-infarct regions may be a specific response to microvascular insults. Given the established OXTR signaling cascades that elicit antioxidant, anti-inflammatory, and pro-angiogenic responses, the present findings suggest that de novo OXTR expression in the peri-infarct space is a tissue-protective response by astroglial and vascular cells in the wake of ischemic damage that could be exploited as a therapeutic option for the preservation of cognition following cerebrovascular insults.
The oxytocin receptor (OXTR) is a G protein-coupled receptor with a diverse repertoire of intracellular signaling pathways, which are activated in response to binding oxytocin (OXT) and a similar ...nonapeptide, vasopressin. This review summarizes the cell and molecular biology of the OXTR and its downstream signaling cascades, particularly focusing on the mnemonic, stress, and vasoactive functions of OXTR signaling in humans and animal models, as well as the clinical applications of OXTR targeting CNS disorders such as cerebrovascular accidents.
Alzheimer's disease (AD) is the most common age-related form of dementia, associated with deposition of intracellular neuronal tangles consisting primarily of hyperphosphorylated ...microtubule-associated protein tau (p-tau) and extracellular plaques primarily comprising amyloid- β (Aβ) peptide. The p-tau tangle unit is a posttranslational modification of normal tau protein. Aβ is a neurotoxic peptide excised from the amyloid-β precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. MicroRNAs (miRNAs) are short, single-stranded RNAs that modulate protein expression as part of the RNA-induced silencing complex (RISC). We identified miR-298 as a repressor of APP, BACE1, and the two primary forms of Aβ (Aβ40 and Aβ42) in a primary human cell culture model. Further, we discovered a novel effect of miR-298 on posttranslational levels of two specific tau moieties. Notably, miR-298 significantly reduced levels of ~55 and 50 kDa forms of the tau protein without significant alterations of total tau or other forms. In vivo overexpression of human miR-298 resulted in nonsignificant reduction of APP, BACE1, and tau in mice. Moreover, we identified two miR-298 SNPs associated with higher cerebrospinal fluid (CSF) p-tau and lower CSF Aβ42 levels in a cohort of human AD patients. Finally, levels of miR-298 varied in postmortem human temporal lobe between AD patients and age-matched non-AD controls. Our results suggest that miR-298 may be a suitable target for AD therapy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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