Cerebral Aß40 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 (Aß) 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 Aß40 into ventricular cerebrospinal fluid modulates blood pressure in the Dahl salt-sensitive rat. The Dahl salt-sensitive rat develops hypertension if given a high-salt diet. Intracerebroventricular infusion of Aß induced a progressive rise in blood pressure in rats with pre-existing hypertension produced by a high-salt diet ( p < 0.0001), but no change in blood pressure in normotensive rats. The elevation in arterial pressure in high-salt rats was associated with an increase in low frequency spectral density in systolic blood pressure, suggesting autonomic imbalance, and reduced cardiac baroreflex gain. Our results demonstrate the potential for intracerebral Aß to exacerbate hypertension, through modulation of autonomic activity. Present findings raise the possibility that mid-life hypertension in people who subsequently develop Alzheimer's disease may in some cases be a physiological response to reduced cerebral perfusion complicating the accumulation of Aß within the brain.

Post-mortem assessment of hypoperfusion of cerebral cortex in Alzheimer's disease and vascular dementia.

Perfusion is reduced in the cerebral neocortex in Alzheimer's disease. We have explored some of the mechanisms, by measurement of perfusion-sensitive and disease-related proteins in post-mortem tissue from Alzheimer's disease, vascular dementia and age-matched control brains. To distinguish physiological from pathological reduction in perfusion (i.e. reduction exceeding the decline in metabolic demand), we measured the concentration of vascular endothelial growth factor (VEGF), a protein induced under conditions of tissue hypoxia through the actions of hypoxia-inducible factors, and the myelin associated glycoprotein to proteolipid protein 1 (MAG:PLP1) ratio, which declines in chronically hypoperfused brain tissue. To evaluate possible mechanisms of hypoperfusion, we also measured the levels of amyloid-ß40, amyloid-ß42, von Willebrand factor (VWF; a measure of microvascular density) and the potent vasoconstrictor endothelin 1 (EDN1); we assayed the activity of angiotensin I converting enzyme (ACE), which catalyses the production of another potent vasoconstrictor, angiotensin II; and we scored the severity of arteriolosclerotic small vessel disease and cerebral amyloid angiopathy, and determined the Braak tangle stage. VEGF was markedly increased in frontal and parahippocampal cortex in Alzheimer's disease but only slightly and not significantly in vascular dementia. In frontal cortex the MAG:PLP1 ratio was significantly reduced in Alzheimer's disease and even more so in vascular dementia. VEGF but not MAG:PLP1 increased with Alzheimer's disease severity, as measured by Braak tangle stage, and correlated with amyloid-ß42 and amyloid-ß42: amyloid-ß40 but not amyloid-ß40. Although MAG:PLP1 tended to be lowest in cortex from patients with severe small vessel disease or cerebral amyloid angiopathy, neither VEGF nor MAG:PLP1 correlated significantly with the severity of structural vascular pathology (small vessel disease, cerebral amyloid angiopathy or VWF). However, MAG:PLP1 showed a significant negative correlation with the level of EDN1, which we previously showed to be elevated in the cerebral cortex Alzheimer's disease. These finding are in contrast with the previously demonstrated reduction in EDN1, and positive correlation with MAG:PLP1, in the hypoperfused white matter in Alzheimer's disease. The decline in MAG:PLP1 strongly suggests pathological hypoperfusion of the frontal cortex in Alzheimer's disease. Although severe small vessel disease or cerebral amyloid angiopathy may contribute in some cases, abnormal vascular contractility mediated by EDN1 is likely to be a more important overall contributor. Both amyloid-ß accumulation and hypoperfusion are likely to cause the upregulation of VEGF.

Elevated matrix metalloproteinase-9 and degradation of perineuronal nets in cerebrocortical multiple sclerosis plaques.

Matrix metalloproteinases (MMPs) degrade extracellular matrix; MMP activity, particularly of MMP-9, is elevated in the white matter in multiple sclerosis (MS) patients. The cerebral cortical extracellular matrix includes perineuronal nets (PNs) that surround parvalbumin-positive neurons (PV-positive neurons) and are important for their function. We measured active and total MMP-9 levels in postmortem homogenates of demyelinated and nondemyelinated cerebral cortical regions from 9MS and 7 control cases and assessed Wisteria floribunda agglutin (WFA)-positive PNs in paraffin sections from 15 MS and 6 controls and PV-positive neurons in sections from 26 MS and 6 controls. Active MMP-9 levels were higher in demyelinated than in nondemyelinated or control cortex (p < 0.05). The area fraction positive for WFA was lower in demyelinated than nondemyelinated MS or control cortex; the latter difference was significant (p < 0.05). Most PV-positive neurons in demyelinated but not intact cortex lackeda PN, and some showed perikaryal phosphorylated neurofilament protein accumulation. Loss of WFA-labeled PNs was not associated with reduced PV-positive neurons numbers. Thus, elevated MMP-9 in cortical plaques is associated with loss of PNs; PV-positive neurons are preserved but show abnormal neurofilament accumulations. Matrix metalloproteinase-mediated degradation of PNs in cortical plaques may, therefore, contribute to neuronal dysfunction and degeneration in MS patients.

Elevated myeloperoxidase activity in white matter in multiple sclerosis.

Recent studies have revealed extensive axonal damage in patients with progressive multiple sclerosis (MS). Axonal damage can be caused by a plethora of factors including the release of proteolytic enzymes and cytotoxic oxidants by activated immune cells and glia within the lesion. Macrophages and microglia are known to express myeloperoxidase (MPO) and generate reactive oxygen species during myelin phagocytosis in the white matter. In the present study we have measured MPO levels in post-mortem homogenates of demyelinated and non-demyelinated regions of white matter from nine patients with MS and seven controls, and assessed MPO immunoreactivity within MS brain. In homogenates of MS white matter, demyelination was associated with significantly elevated MPO activity when compared to controls. Immunohistochemistry showed MPO to be expressed mainly by macrophages within and adjacent to plaques. Demyelination in MS is associated with increased activity of MPO, suggesting that this production of reactive oxygen species may contribute to axonal injury within plaques.

Elevated activity and microglial expression of myeloperoxidase in demyelinated cerebral cortex in multiple sclerosis.

Recent studies have revealed extensive cortical demyelination in patients with progressive multiple sclerosis (MS). Demyelination in gray matter lesions is associated with activation of microglia. Macrophages and microglia are known to express myeloperoxidase (MPO) and generate reactive oxygen species during myelin phagocytosis in the white matter. In the present study we examined the extent of microglial activation in the cerebral cortex and the relationship of microglial activation and MPO activity to cortical demyelination. Twenty-one cases of neuropathologically confirmed multiple sclerosis, with 34 cortical lesions, were used to assess microglial activation. HLA-DR immunolabeling of activated microglia was significantly higher in demyelinated MS cortex than control cortex and, within the MS cohort, was significantly greater within cortical lesions than in matched non-demyelinated areas of cortex. In homogenates of MS cortex, cortical demyelination was associated with significantly elevated MPO activity. Immunohistochemistry revealed MPO in CD68-positive microglia within cortical plaques, particularly toward the edge of the plaques, but not in microglia in adjacent non-demyelinated cortex. Cortical demyelination in MS is associated with increased activity of MPO, which is expressed by a CD68-positive subset of activated microglia, suggesting that microglial production of reactive oxygen species is likely to be involved in cortical demyelination.