The Presence, Origin, and Significance of Aβ Peptide in the Cell Bodies of Neurons

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Abstract
Interest in the Aβ amyloid in Alzheimer disease (AD) has largely focused on the Aβ in the neuropil, an extracellular site. Here much attention has been given to the possibility that Aβ acts as a neurotoxin. However, increasing emphasis is now being given to the relationship between neurofibrillary tangles (NFT) and the degree of cognitive decline, as opposed to the relationship between decline and senile plaques, the sites of extracellular Aβ deposition. This review focuses attention on the existence and significance of Aβ in the cell body of the neuron. The review brings together diverse strands of literature indicating: (1) the tau-positive, paired helical filaments that are the main component of NFT are not themselves the source of the amyloid-like staining (Congo red birefringence) of PHF, and are not, in fact, an “amyloid”; (2) there is Aβ within the cytoplasm of neurons affected by AD and in other conditions characterized by tau-positive neurofibrillary tangles; (3) peptides derived from portions of the Aβ precursor can bind to PHF; (4) the affected neurons are the source of extracellular Aβ in their vicinity and are also unable to maintain the synaptic structures that depend upon the integrity of the neuronal cell body; and (5) debates about whether the intracellular Aβ is an amyloid depend upon beliefs about its tertiary structure and assumptions concerning the relationship between the size of self-aggregating Aβ molecules, their tertiary structure, and their ability to generate Congo red birefringence without necessarily being detected as ultrastuctural filaments 5–10 nm wide. Based upon this literature, it is suggested that the Congo red birefringence generated by NFT is caused by Aβ, intimately bound to the NFT. Moreover, whether defined as an amyloid or not, the Aβ in the neuronal cell body indicates an abnormal processing of the precursor molecule on the way to its ultimate transmembrane domain. Deranged neuronal functioning, which leads to this abnormal processing and/or the intracellular Aβ itself, may be the cause of subsequent functional and morphologic abnormalities in the brain.

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