P1‐084: Role of the nested genes ALZAS and ALZAS‐1 in Alzheimer's disease

Plaques and tangles, markers of Alzheimer disease (AD), may not lead to synapse and neuronal dysfunction. Alternative pathogenic factors include inflammation, oxidative stress, membrane alterations, blood-brain-barrier (BBB) disorders. Two recently discovered nested genes ALZAS and ALZAS-1 (ALZheimer ASsociated) are located within the APP (amyloid precursor protein) region on chromosome 21; ALZAS contains a complete sequence of Aß42. A specific auto antibody against the 12 c-terminal amino acids (ct-12) of ALZAS derived from an intron part of APP was identified by ELISA methods. ALZAS peptide was investigated by Western Blotting using a specific antibody against ct-12. To test the feasible induction and function of ALZAS and ALZAS-1 both genes were cloned in a suitable inducible mammalian expression vector with subsequent transfection in human cell lines. High auto antibody titers occurred in pre-symptomatic AD or mild cognitive impairment (MCI), moderate ones in confirmed AD. Cognitively unimpaired controls showed low or not detectable titers. Analysis of the mRNA levels of ALZAS and ALZAS-1 indifferent tissues (brain, heart, liver, blood) revealed tissue dependent expression. While the brain showed no significant differences between AD and controls, higher levels of ALZAS peptide were observed in controls. In heart and liver small protein oligomeres were identified; in all other tissues tested so far ALZAS seems to exist as a larger oligomere. ALZAS / ALZAS-1 immunohistochemistry in human post mortem AD brain with a polyclonal rabbit ct-12 antibody revealed prominent intraneuronal staining of pyramid neurons in frontal cortex different from Aß42plaques. ALZAS staining of brain capillaries and detection of fibrinogen in parenchyma may indicate an increased BBB permeability and membrane damage. An overall transcription of ALZAS and ALZAS-1 in peripheral tissues and unaltered mRNA expression in brains of controls and AD were observed. The expression of these nested genes may be triggered by still unknown factors to be modulated in tg human cell cultures. Nested genes seem to participate in cellular signal transduction. ALZAS rather than APP maybe a source of soluble intraneuronal Aß inducing synaptic pathology and neuronal loss.