Dysregulation of the renin-angiotensin system in vascular dementia.

The renin-angiotensin system (RAS) regulates systemic and cerebral blood flow and is dysregulated in dementia. The major aim of this study was to determine if RAS signalling is dysregulated in vascular dementia. We measured markers of RAS signalling in white matter underlying the frontal and occipital cortex in neuropathologically confirmed cases of vascular dementia (n = 42), Alzheimer's disease (n = 50), mixed AD/VaD (n = 50) and age-matched controls (n = 50).

Altered Gene Expression Within the Renin-Angiotensin System in Normal Aging and Dementia.

The renin-angiotensin system (RAS) is dysregulated in Alzheimer's disease (AD). In this study, we have explored the hypothesis that an -age--related imbalance in brain RAS is a trigger for RAS dysregulation in AD. We characterized RAS gene expression in the frontal cortex from (i) a cohort of normal aging (n = 99, age range = 19-96 years) and (ii) a case-control cohort (n = 209) including AD (n = 66), mixed dementia (VaD + AD; n = 50), pure vascular dementia (VaD; n = 42), and age-matched controls (n = 51).

Elevated late-life blood pressure may maintain brain oxygenation and slow amyloid-β accumulation at the expense of cerebral vascular damage.

Hypertension in midlife contributes to cognitive decline and is a modifiable risk factor for dementia. The relationship between late-life hypertension and dementia is less clear. We have investigated the relationship of blood pressure and hypertensive status during late life (after 65 years) to post-mortem markers of Alzheimer's disease (amyloid-β and tau loads); arteriolosclerosis and cerebral amyloid angiopathy; and to biochemical measures of ante-mortem cerebral oxygenation (the myelin-associated glycoprotein:proteolipid protein-1 ratio, which is reduced in chronically hypoperfused brain tissue, and the level of vascular endothelial growth factor-A, which is upregulated by tissue hypoxia); blood-brain barrier damage (indicated by an increase in parenchymal fibrinogen); and pericyte content (platelet-derived growth factor receptor β, which declines with pericyte loss), in Alzheimer's disease ( = 75), vascular ( = 20) and mixed dementia ( = 31) cohorts.

Mediators of cerebral hypoperfusion and blood-brain barrier leakiness in Alzheimer's disease, vascular dementia and mixed dementia.

In vascular dementia (VaD) and Alzheimer's disease (AD), cerebral hypoperfusion and blood-brain barrier (BBB) leakiness contribute to brain damage. In this study, we have measured biochemical markers and mediators of cerebral hypoperfusion and BBB in the frontal (BA6) and parietal (BA7) cortex and underlying white matter, to investigate the pathophysiology of vascular dysfunction in AD, VaD and mixed dementia. The ratio of myelin-associated glycoprotein to proteolipid protein-1 (MAG:PLP1), a post-mortem biochemical indicator of the adequacy of ante-mortem cerebral perfusion; the concentration of fibrinogen adjusted for haemoglobin level, a marker of blood-brain barrier (BBB) leakiness; the level of vascular endothelial growth factor-A (VEGF), a marker of tissue hypoxia; and endothelin-1 (EDN1), a potent vasoconstrictor, were measured by ELISA in the frontal and parietal cortex and underlying white matter in 94 AD, 20 VaD, 33 mixed dementia cases and 58 age-matched controls.

Zibotentan, an Endothelin A Receptor Antagonist, Prevents Amyloid-β-Induced Hypertension and Maintains Cerebral Perfusion.

Cerebral blood flow is reduced in Alzheimer's disease (AD), which is associated with mid-life hypertension. In people with increased cerebral vascular resistance due to vertebral artery or posterior communicating artery hypoplasia, there is evidence that hypertension develops as a protective mechanism to maintain cerebral perfusion. In AD, amyloid-β (Aβ) accumulation may similarly raise cerebral vascular resistance by upregulation of the cerebral endothelin system.

Systemic infection modifies the neuroinflammatory response in late stage Alzheimer's disease.

Clinical studies indicate that systemic infections accelerate cognitive decline in Alzheimer's disease. Animal models suggest that this may be due to enhanced pro-inflammatory changes in the brain. We have performed a post-mortem human study to determine whether systemic infection modifies the neuropathology and in particular, neuroinflammation, in the late-stage of the disease.

Cerebral Aβ and systemic hypertension.

Mid-life hypertension and cerebral hypoperfusion may be preclinical abnormalities in people who later develop Alzheimer's disease. Although accumulation of amyloid-beta (Aβ) is characteristic of Alzheimer's disease and is associated with upregulation of the vasoconstrictor peptide endothelin-1 within the brain, it is unclear how this affects systemic arterial pressure. We have investigated whether infusion of Aβ into ventricular cerebrospinal fluid modulates blood pressure in the Dahl salt-sensitive rat.

Synaptic protein levels altered in vascular dementia.

Introduction: Cerebral ischaemia is the defining pathophysiological abnormality in most forms of vascular dementia (VAD), but the pathogenesis of the dementia remains poorly understood. In Alzheimer's disease (AD), there is early loss of synaptic proteins, but these have been little studied in VAD.

Materials And Methods: We measured synaptophysin, postsynaptic density protein 95 (PSD-95), drebrin, synaptosomal-associated protein 25 (SNAP-25) and vascular endothelial growth factor (VEGF) by enzyme-linked immunosorbent assays in superior temporal cortex from 11 patients with VAD and, initially, 11 non-dementia controls.

Aβ degradation or cerebral perfusion? Divergent effects of multifunctional enzymes.

There is increasing evidence that deficient clearance of β-amyloid (Aβ) contributes to its accumulation in late-onset Alzheimer disease (AD). Several Aβ-degrading enzymes, including neprilysin (NEP), endothelin-converting enzyme (ECE), and angiotensin-converting enzyme (ACE) reduce Aβ levels and protect against cognitive impairment in mouse models of AD. In post-mortem human brain tissue we have found that the activity of these Aβ-degrading enzymes rise with age and increases still further in AD, perhaps as a physiological response that helps to minimize the build-up of Aβ.

Endothelin-converting enzyme-1 activity, endothelin-1 production, and free radical-dependent vasoconstriction in Alzheimer's disease.

Alzheimer's disease (AD) patients have reduced cerebral blood flow. This precedes dementia and may contribute to its progression. In mice that overexpress amyloid-β protein precursor, cerebral blood flow declines before the development of plaques or cognitive abnormalities.

Oxidative balance in Alzheimer's disease: relationship to APOE, Braak tangle stage, and the concentrations of soluble and insoluble amyloid-β.

Oxidative damage is greater in brain tissue from patients with Alzheimer's disease (AD) than age-matched controls. The timing of this damage in relation to other pathogenic processes in AD remains unclear. We have examined the relationship of lipid peroxidation (thiobarbituric acid-reactive substances; TBARS) and antioxidant capacity (Trolox-equivalent) to APOE status, Braak tangle stage, amyloid-β (Aβ) plaque load, and the concentration of soluble and insoluble forms of Aβ, post-synaptic and dendritic spine proteins PSD95 and drebrin, β-secretase and Aβ-degrading enzymes neprilysin (NEP), insulin-degrading enzyme (IDE), and angiotensin-converting enzyme (ACE), in frontal, temporal, and parietal cortex from AD and control brains.

Distribution and expression of picalm in Alzheimer disease.

PICALM, the gene encoding phosphatidylinositol-binding clathrin assembly (picalm) protein, was recently shown to be associated with risk of Alzheimer disease (AD). Picalm is a key component of clathrin-mediated endocytosis. It recruits clathrin and adaptor protein 2 (AP-2) to the plasma membrane and, along with, AP-2 recognizes target proteins.

Angiotensin-converting enzyme levels and activity in Alzheimer's disease: differences in brain and CSF ACE and association with ACE1 genotypes.

Angiotensin-converting enzyme (ACE) has been implicated in Alzheimer's disease (AD): ACE1 variations influence plasma ACE and risk of AD, and ACE is increased in AD brain. We measured frontal ACE level and activity in 89 AD and 51 control brains, and post-mortem CSF from 101 cases and 19 controls. Neuron-specific enolase (NSE) level and Braak stage were used to indicate neuronal preservation and disease progression.

Fatty acid composition of frontal, temporal and parietal neocortex in the normal human brain and in Alzheimer's disease.

Dietary omega3-polyunsaturated fatty acids are thought to influence the risk of Alzheimer's disease (AD), and supplemental docosahexaenoic acid (DHA; 22:6n-3) has been reported to reduce neurodegeneration in mouse models of AD. We have analysed the fatty acid composition of frontal, temporal and parietal neocortex in 58 normal and 114 AD brains. Significant reductions were found for stearic acid (18:0) in frontal and temporal cortex and arachidonic acid (20:4n-6) in temporal cortex in AD, and increases in oleic acid in frontal and temporal cortex (18:1n-9) and palmitic acid (16:0) in parietal cortex.

Neprilysin and insulin-degrading enzyme levels are increased in Alzheimer disease in relation to disease severity.

Experimental reduction of neprilysin (NEP) or insulin-degrading enzyme (IDE) in vivo exacerbates beta-amyloid accumulation in the brain. The level of these enzymes is reportedly reduced during aging and in postmortem brains of patients with sporadic Alzheimer disease (AD). To distinguish between primary decreases in NEP and IDE activity that might contribute to beta-amyloid accumulation and decreases secondary to neurodegenerative changes in AD, we measured NEP and IDE levels by indirect sandwich ELISA and enzyme activities by immunocapture-based fluorogenic assays in postmortem frontal cortex from patients of different ages and at different pathological stages of AD, as indicated by Braak tangle stage.

Low-temperature improved-throughput method for analysis of brain fatty acids and assessment of their post-mortem stability.

Deficiency of docosahexaenoic acid (DHA) and other omega-3 (omega3) fatty acids may constitute an alterable risk factor for Alzheimer's disease (AD). Mechanisms of potential involvement of DHA in the disease process have been postulated primarily from studies in vitro and in mouse models of AD. Information on the fatty acid profile of the brain in AD itself is limited and in some respects contradictory.