Intra- and extracellular Aβ and PHF in clinically evaluated cases of Alzheimer's disease

Temporal cortical sections from postmortem brains of individuals without any dementing condition and with different degrees of severity of Alzheimer’s disease (AD) evaluated by the Clinical Dementia Rating scale (CDR 0-CDR 3) were analyzed using immunohistochemical procedures. To demonstrate the amyloid-s-peptide (As) deposition and the neurofibrillary pathology, two monoclonal antibodies were used, a human CERAD As (10D5) antibody raised against the N-terminal region of the As-peptide, and an antibody raised against paired helical filaments (PHF-1). The neuron cell bodies and the glial cells were also recognized by two polyclonal antibodies raised, respectively, against the protein gene peptide (PGP 9.5) and glial fibrillary acidic protein (GFAP). Directly related to severity of AD, progressive deposits of Aspeptide were found within cortical pyramidal-like neurons and forming senile plaques. Ultrastructurally, As-peptide deposits were related to neuronal intracytoplasmic organelles, such as the ER, the mitochondria, the Nissl bodies and lipofuscin. We have also found that the intracellular deposition of the As peptide is a neuropathological finding prior to the appearance of PHF-immunoreactive structures. We suggest that the intracellular As deposition in cortical pyramidal neurons is a first neurodegenerative event in AD development and that it is involved in cell dysfunction, neuronal death, and plaque formation