Intraneuronal A beta Immunoreactiviy is not a predictor of brain amyloldosls- beta or neurofibrillary degeneration

• Published in: Acta neuropathologica 2007-04, Vol.113 (4), p.389-402
• Main Authors: Wegiel, J, Kuchna, I, Nowicki, K, Frackowiak, J, Mazur-Kolecka, B, Imaki, H, Mehta, P D, Silverman, W P, Reisberg, B, deLeon, M, Wisniewski, T, Pirttilla, T, Frey, H
• Format: Article
• Language: English
• ISSN: 0001-6322
• DOI: 10.1007/s00401-006-0191-4

Amyloid beta (A beta ) immunoreactivity in neurons was examined in brains of 32 control subjects, 31 people with Down syndrome, and 36 patients with sporadic Alzheimer's disease to determine if intraneuronal A beta immunoreactivity is an early manifestation of Alzheimer-type pathology leading to fibrillar plaque formation and/or neurofibrillary degeneration. The appearance of A beta immunoreactivity in neurons in infants and stable neuron-type specific A beta immunoreactivity in a majority of brain structures during late childhood, adulthood, and normal aging does not support this hypothesis. The absence or detection of only traces of reaction with antibodies against 4-13 aa and 8-17 aa of A beta in neurons indicated that intraneuronal A beta was mainly a product of alpha - and gamma -secretases (A beta sub(17-40/42)). The presence of Nterminally truncated A beta sub(17-40) and A beta sub(17-42) in the control brains was confirmed by Western blotting and the identity of A beta sub(17-40) was confirmed by mass spectrometry. The prevalence of products of alpha - and gamma -secretases in neurons and beta - and gamma -secretases in plaques argues against major contribution of A beta -immunopositive material detected in neuronal soma to amyloid deposit in plaques. The strongest intraneuronal A beta sub(17-42) immunoreactivity was observed in structures with low susceptibility to fibrillar A beta deposition, neurofibrillary degeneration, and neuronal loss compared to areas more vulnerable to Alzheimer-type pathology. These observations indicate that the intraneuronal A beta immunoreactivity detected in this study is not a predictor of brain amyloidosis or neurofibrillary degeneration. The constant level of A beta immunoreactivity in structures free from neuronal pathology during essentially the entire life span suggests that intraneuronal amino-terminally truncated A beta represents a product of normal neuronal metabolism.