Target for a New Generation of Therapeutic Agents

Kimby N. Barton, MSc
Assistant Editor,
Geriatrics & Aging

The small southern Italian village of Nicastro, once again made it into International headlines when researchers at the University of Toronto discovered a new protein, nicastrin, which is involved in Alzheimer's disease (AD). Nicastrin was so named to honour a large family in Nicastro that has been plagued with AD for generations and played a key role in the 1995 discovery of two genes that cause early onset Alzheimer's. The same team, led by Peter St. George Hyslop, has found that nicastrin is a functional component of the g-secretase, which is involved in the formation of toxic plaques found in the brains of AD patients. More importantly, they have found an exposed and highly conserved domain of this protein that affects production of the amyloid-b (Ab) peptide and may serve as a potential target for pharmaceutical modulation of Ab production in patients with AD and other related disorders.

Much of the research into AD has been focused on the mechanism underlying the formation of the (Ab) peptide, which is a key component of the toxic amyloid plaques that are characteristic of brain tissue from patients with AD. In 1995, it was discovered that a mutation in a previously unknown protein could lead to an early-onset form of familial AD. This protein was subsequently discovered to be presenilin, a highly conserved, polytopic membrane protein. However, several studies have demonstrated that although mutations in presenilin may result in overproduction of the toxic Ab derivative, it is unlikely that the protein acts alone.

The Ab peptide is generated from a large precursor protein, the amyloid precursor protein (APP) in a two-step proteolytic pathway. Initially, the protein is cleaved near the cell surface in an extracellular domain either by a b- or a a-secretase to generate C-terminal stubs of the protein. These stubs are then further cleaved in their transmembrane domains by the presenilin-linked g-secretase to generate two different isoforms of the Ab peptide, one that is benign and one that is neurotoxic. The b-secretase enzyme appears to have a benign role; during development it may cleave a protein called Notch, which releases a fragment that activates gene transcription. Unfortunately it has been difficult to determine which proteins are directly responsible for the g-secretase activity, although evidence suggests that the presenilins are involved.

St. George-Hyslop's tream found that nicastrin binds to presenilins 1 and 2 and interacts with the APP carboxy terminal 'stub', the fragment that is produced by the initial, b-secretase cleavage. Mutations in an exposed and conserved domain of nicastrin, increase the production of both forms of the Ab peptide and deletions inhibit their production. The team also found that nicastrin is required for processing of the protein Notch, which is involved in gene activation.

So, nicastrin is structurally part of the g-secretase complex, but how does it interact with the other proteins? The team has suggested that nicastrin may bind to the APP stub and align it in the correct way to presenilin, so that it is cleaved at the right position. Another possibility is that nicastrin regulates the cleavage activity, in which case, compounds that interact with either nicastrin or the presenilins should effectively alter g-secretase and APP turnover; hence a site for pharmaceutical intervention.

Whether or not genetic variants in nicastrin are associated with inherited susceptibility to AD remains to be determined. Research in this field will be ongoing, but in the meantime pharmaceutical companies will no doubt devote a great deal of attention to this little 'Italian' protein.