Deposition of the β-amyloid peptide (Aβ) in the brain occurs during normal ageing and is substantially accelerated in patients with Alzheimer's disease. Since Aβ is continuously produced in the brain, it has been suggested that a clearance mechanism should exist to prevent its accumulation and subsequent aggregation. Until now, little attention has been paid to the possible role of P-glycoprotein (P-gp), a member of the ATP binding cassette superfamily of transporter proteins, in the pathogenesis of Alzheimer's disease. A recent study demonstrated in vitro that Aβ40 and Aβ42 interact directly with P-gp. We therefore hypothesized that Aβ accumulation in the brain would correlate inversely with the degree of vascular P-gp expression. To study early pathogenetic factors that influence the deposition of Aβ, at routine autopsies, brain tissue samples were taken from 243 non-demented subjects who died between the ages of 50 and 91 years. Vascular P-gp expression and the number of Aβ40- and Aβ42-positive senile plaques were assessed immunohistochemically in the medial temporal lobe. In addition, the apolipoprotein E (apoE) genotypes, as well as multiple drug resistance gene 1 (MDR1) polymorphisms (exon 2, G–1A; exon 21, G2677T/A; exon 26, C3436T), were also determined for each case. P-gp expression was not correlated with MDR1 genotypes, but we found a significant inverse correlation between P-gp expression and the deposition of both Aβ40 and Aβ42 in the medial temporal lobe. Our results provide the first evidence in human brain tissue that the accumulation of Aβ may be influenced by the expression of P-gp in blood vessels, and suggest that P-gp may influence the elimination of Aβ from brain.

PrPC‐deficient mice expressing prion protein variants with large amino‐proximal deletions (termed PrPΔF) suffer from neurodegeneration, which is rescued by full‐length PrPC. We now report that expression of PrPΔCD, a PrP variant lacking 40 central residues (94–134), induces a rapidly progressive, lethal phenotype with extensive central and peripheral myelin degeneration. This phenotype was rescued dose‐dependently by coexpression of full‐length PrPC or PrPC lacking all octarepeats. Expression of a PrPC variant lacking eight residues (114–121) was innocuous in the presence or absence of full‐length PrPC, yet enhanced the toxicity of PrPΔCD and diminished that of PrPΔF. Therefore, deletion of the entire central domain generates a strong recessive‐negative mutant of PrPC, whereas removal of residues 114–121 creates a partial agonist with context‐dependent action. These findings suggest that myelin integrity is maintained by a constitutively active neurotrophic protein complex involving PrPC, whose effector domain encompasses residues 94–134.

In Alzheimer disease (AD), the intracerebral accumulation of amyloid-β (Aβ) peptides is a critical yet poorly understood process. Aβ clearance via the blood-brain barrier is reduced by approximately 30% in AD patients, but the underlying mechanisms remain elusive. ABC transporters have been implicated in the regulation of Aβ levels in the brain. Using a mouse model of AD in which the animals were further genetically modified to lack specific ABC transporters, here we have shown that the transporter ABCC1 has an important role in cerebral Aβ clearance and accumulation. Deficiency of ABCC1 substantially increased cerebral Aβ levels without altering the expression of most enzymes that would favor the production of Aβ from the Aβ precursor protein. In contrast, activation of ABCC1 using thiethylperazine (a drug approved by the FDA to relieve nausea and vomiting) markedly reduced Aβ load in a mouse model of AD expressing ABCC1 but not in such mice lacking ABCC1. Thus, by altering the temporal aggregation profile of Aβ, pharmacological activation of ABC transporters could impede the neurodegenerative cascade that culminates in the dementia of AD.