The Ultrastructural Identity of Alzheimer’s Pathology: Lessons from Animal Models

Abstract

Dr. Alois Alzheimer was an accomplished histopathologist. At the time of his November 1906 lecture in Tubingen, Germany, where he presented the case of his patient Augustine D, he had spent many years in the histology lab. Four years earlier, the “Bielschowsky” silver staining method was developed and nearly a decade before Santiago Ramon y Cajal had perfected Camillo Golgi’s silver staining method. These techniques were crucial for the identification of the neuritic plaques and tangles in Frau Augustine’s brain. Almost 60 years later, after thousands of histopathological slides were examined by conventional light microscopy, electron microscopy (EM) began to reveal new facets of this disease by unraveling the submicroscopic structure of AD pathology. Terry, Kidd and Wisniewski published the first detailed reports of postmortem AD brains ultrastructure. Senile plaques were described of being composed of extracellular deposits of an amyloid-β (Aβ) “central fibrillar core”, surrounded by “axons and dendrites filled with an excess of neurofibrils”, and “cell processes filled with dense bodies” along with a halo of glial cells. The earliest signs of plaque formation, the “diffuse plaque” and amyloid deposition in AD-related angiopathy were later described. The progressive decrease in synaptic numbers in humans was documented. Neurofibrillary tangles (NFT) were shown to be formed by paired helical filaments (PHF). Scanning EM was also applied with great success for the study of PHF. After the identification of plaque filaments it took two decades before their major components were known. Since 1996, only few systemic human EM studies have been published.