Analyses of the plaques and neuronal fibrillary changes have been undertaken in an attempt to elucidate the mechanism of Alzheimer disease, but so far, to little avail beyond implicating one or both in the accompanying neuronal degeneration. Several histologic techniques assist in this endeavor, including refined methods for silver impregnation that stain both amyloid and its main constituent (beta-amyloid protein [Aβ]); immunostaining using antibodies specific to such proteins as ubiquitin, neuronal tau protein, and β-amyloid protein; and visualization of β-pleated protein sheets using thioflavine S and in the past especially, Congo red with ultraviolet and polarized light. Tau (composed chemically of β2-transferrin) is a discrete cytoskeletal protein that promotes the assembly of microtubules, stabilizes their structure, and participates in synaptic plasticity in a yet to be defined manner. In the pathologic circumstances of Alzheimer disease, progressive supranuclear palsy, and one form of frontotemporal dementia (see further on), tau is hyperphosphorylated and aggregates, resulting in paired helical filaments that make up the neurofibrillary tangles. Electrophoretically, tau moves with the β2-globulins and functions as a transferrin, that is, it binds iron and delivers it to the cell. Its concentration can be measured in the CSF and serum, but this has not yet proven clearly to be useful as a diagnostic test or to offer understanding of the pathogenesis of the disease.
The Aβ (beta amyloid) protein is a small portion of a larger entity, the amyloid precursor protein (APP), which is normally bound to neuronal membranes. As shown schematically in Fig. 38-2, the Aβ protein is cleaved from APP by the action of proteases termed α, β, and γ secretase. One current hypothesis focuses on the manner in which APP is cleaved by these enzymes to give rise to different-length residues of Aβ. During normal cellular metabolism, APP is cleaved by either α or β secretase. The products of this reaction are then cleaved by the γ-secretase isoform of the enzyme. The sequential cleavage by α and then γ produces tiny fragments that are not toxic to neurons. However, cleavage by β and then γ results in a 40-amino-acid product, Aβ40, and a longer 42-amino-acid form. The latter Aβ42 form is toxic in several models of Alzheimer disease, and it has been proposed that the ratio of Aβ42 to Aβ40 is critical to the neuronal toxicity of amyloid.
Several pieces of evidence favor the view that elevation of the levels of Aβ42 leads to aggregation of amyloid and then to neuronal toxicity. This is currently the most often cited hypothesis for the genesis of the disease. It appears that the diffuse deposition of Aβ42 precedes the formation of better-defined neurofibrils and plaques.