One Solution Structure of the b-Amyloid Protein

This nmr derived structure is largely helical; other structures vary significantly with solvent. and are chiefly random coil. The aggregate is believed to form from a b-strand, which has never been observed experimentally.

The precursor protein, called Alzheimer's precursor protein (APP) is a membrane protein, the tertiary structure of which is unknown, although it has been sequenced.

Sequence Alignment of b=Amyloid and APP

APP is cleaved by a protease component of a trans-membrane complex called secretase; the protease is sometimes called b-secretase, sometimes memepsin.

• Normally, the fragments of APP are dumped inside the cell and destroyed.

• In Alzheimer's, they are dumped outside, where the b-fragment creates plaque.

No satisfactory explanation of the change is available.

Surpise. Memepsin is an aspartate protease.

b-Secretase (memepsin; 1w50)

Note the characteristic bilobal structure (gene fusion?) of the enzyme, and the pair of catalytic aspartates, Asp32 and Asp228.

Surprise. A considerable enterprise in fighting Alzheimer's is the attempt to inhibit b-secretase. A crystal structure is available of the enzyme inhibited with a polypeptide:

b-Secretase with OM99	Closeup of Catalytic Site

The binding is very similar to other aspartate preotease inhibitors: the peptide lies across only one of the aspartates.

The tangles are formed of tau protein, which normally is associated with neoronal microtubules, and supports the growth of axons.

• In Alzheimeer disease, tau becomes excessively phosphorylated and loses the ability to bind to tubules

• It then aggregates intopaired helical filaments which become tangled

• Humans express six isoforms of tau, ranging from 352 to 441 residues

• The have a very high content of basic and hydrophilic residues, as seen in this alignment of human and bovine tau: