What is amyloid? Which amyloids accumulate in Alzheimer’s? How dose amyloid cause disease?

Amyloid in other diseases. There are many diseases, mostly terminal that are associated with accumulation of amyloid. Amyloid is a term used to describe any protein that aggregates or precipitates abnormally in a beta pleated sheet. Our hair is actually a protein in a beta-pleated sheet, but it is outside the body, so it does not impair function in the body. Proteins that typically form amyloid are those that aggregate (stick to themselves). Diseases that you know that are amyloid disease are Mad Cow disease (where the protein prion forms amyloid) and myeloma (where antibodies form amyloid).

Tau and beta-protein are the two proteins that form  amyloid in Alzheimer’s. In Alzheimer’s brain, there are two proteins that form amyloid: tau (the cytoskeletal protein of  the nerve cell or neuron) and beta-protein (also known as beta-amyloid, a normal protein synthesized by all cells and a precursor of a larger membrane protein called amyloid-precursor protein). Amyloid-precursor protein appears to have normal functions important for cells, and the small beta-protein.

What is the reason for so much focus on the small peptide known as beta-amyloid or beta-protein?. Although the tau protein which accumulates in and comprises the neurofibrillary tangle lesion is important in the disease process, it is not genetically linked to the disease.  Tangles form in dementia pugilisitica and in Boxer’s dementia, and mutations in tau can contribute to a frontal temporal dementia (FTD.  However, there are several mutations in the precursor protein for beta-amyloid that can cause the disease, which is why it is thought its dysregulation is critical to triggering the disease process, including the development of tangles.

Insoluble or fibrillary amyloid (the neuritic plaques)

The insoluble fibrillar beta amyloid lesions (known as neuritic plaques) were first described in 1907 by Dr. Alzheimer) and the 42 amino acid protein sequenced by George Glenner in the 1980’s . Surprisingly these plaques do not necessarily correlate very well with disease progression, suggesting that are not directly causal. They could be a tombstome of nerve damage and could also contribute to aberrant sprouting (eg. sprouting of nerve cells without correct synaptic connection to other cells).

 Soluble Beta-Amyloid or Oligomers. The soluble form of amyloid seems to better correlate with disease progression. It appears that high MW weight oligomers may cause synaptic loss. Our laboratory was the first to describe the toxicity of oligomers in vivo at the International Conference in Amsterdam in 1996. We believe that oligomers can be subdivided into different species that do different things, some that cause nerve cell loss some that cause  synaptic loss and others that cause ‘noise’ or distraction. We are trying to decipher the different kinases involved in the different pathways.