Sj Tyler

alpha- and beta-secretase: profound changes in Alzheimer's disease.

The amyloid plaque, a neuropathological hallmark of Alzheimers disease, is produced by the deposition of beta-amyloid (Abeta) peptide, which is cleaved from Amyloid Precursor Protein (APP) by the enzyme beta-secretase. Only small amounts of Abeta form in normal brain; more typically this is precluded by the processing of APP by alpha-secretase. Here, we describe a decrease in alpha-secretase (81% of normal) and a large increase in beta-secretase activity (185%) in sporadic Alzheimers disease temporal cortex. Since alpha-secretase is present principally in neurons known to be vulnerable in Alzheimers disease, and there is known competition between alpha- and beta-secretase for the substrate APP, it is significant that the majority of Alzheimer samples tested here were low in alpha-secretase. Eighty percent of Alzheimer brains examined had an increase in beta-secretase, a decrease in alpha-secretase, or both; which may account for the means by which the majority of people develop Alzheimers disease.

Reduced cholinergic function in normal and Alzheimer's disease brain is associated with apolipoprotein E4 genotype

Apolipoprotein E (ApoE) is a potent risk factor for Alzheimers disease. Since the loss of cholinergic function in Alzheimers disease is known to occur at an early stage in the disease we have examined this function in normal subjects with an Apoepsilon4 allele to see if the deficit occurs in the absence of Alzheimer pathology or symptoms. We report that brain tissue obtained post-mortem from normal subjects and Alzheimer patients with an Apoepsilon4 allele has a lower cholinergic activity than tissue from those subjects without this allele. This has important significance for the interpretation of the cholinergic deficits found in Alzheimers disease.