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Background: Cerebral ionic homeostasis impairment, especially Ca2+, has been observed in Alzheimer's disease (AD) and also with hypertension. Hypertension and AD both have been implicated in impaired cerebral autoregulation. However, the relationship between the ionic homeostasis impairment inADand hypertension and cerebral blood flow(CBF) autoregulation is not clear. Objective: To test the hypothesis that a high-salt diet regimen influences the accumulation of amyloid-β (Aβ) and CBF, exacerbates cognitive decline, and increases the propensity to AD. Methods: Double transgenic mice harboring the amyloid-β protein precursor (APPswe), and presenilin-1 (PSEN1) along with control littermates, 2 months of age at initiation of special diet, were divided into 4 groups: Group A, APP/PS1 and Group B, controls fed a high-sodium (4.00%) chow diet for 3 months; Group C, APP/PS1 and Group D, controls fed a low-sodium (0.08%) regular chow diet for 3 months. Mean arterial blood pressure (MAP) and CBF were measured noninvasively using the tail MAP measurement device and magnetic resonance imaging, respectively. Aβ plaques numbers in the cortex and hippocampus of APP/PS1 were quantified. Results: In contrary to controls, APP/PS1 mice fed a high-salt diet did not showmarkedly elevated mean systolic and diastolic blood pressure (134±4.8 compared with 162±2.8 mmHg, and 114±5.0 compared with 137±20 mmHg, p < 0.0001). However, a high-salt diet increased CBF in both APP/PS1 and controls and did not alter the cerebral tissue integrity. Aβ plaques were significantly reduced in the cortex and hippocampus of mice fed a high-salt diet. Conclusion: These data suggest that a high-salt diet differently affects MAP and CBF in APP/PS1 mice and controls. [ABSTRACT FROM AUTHOR]

The cysteine protease cathepsin B is a potential drug target for reducing brain amyloid-β (Aβ) and improving memory in Alzheimer's disease (AD), as reduction of cathepsin B in transgenic mice expressing human wild-type amyloid-β protein precursor (AβPP) results in significantly decreased brain Aβ. Cathepsin B cleaves the wild-type β-secretase site sequence in AβPP to produce Aβ, and cathepsin B inhibitors administered to animal models expressing AβPP containing the wild-type β-secretase site sequence reduce brain Aβ in a manner consistent with β-secretase inhibition. But such inhibitors could act either by direct inhibition of cathepsin B β-secretase activity or by off-target inhibition of the other β-secretase, the aspartyl protease BACE1. To evaluate that issue, we orally administered a cysteine protease inhibitor, E64d, to normal guinea pigs or transgenic mice expressing human AβPP, both of which express the human wild-type β-secretase site sequence. In guinea pigs, oral E64d administration caused a dose-dependent reduction of up to 92% in brain, CSF, and plasma of Aβ40 and Aβ42, a reduction of up to 50% in the C-terminal β-secretase fragment (CTFβ), and a 91% reduction in brain cathepsin B activity, but increased brain BACE1 activity by 20%. In transgenic AD mice, oral E64d administration improved memory deficits and reduced brain Aβ40 and Aβ42, amyloid plaque, brain CTFβ, and brain cathepsin B activity, but increased brain BACE1 activity. We conclude that E64d likely reduces brain Aβ by inhibiting cathepsin B and not BACE1 β-secretase activity and that E64d therefore may have potential for treating AD patients. [ABSTRACT FROM AUTHOR]