Expression of endothelial and inducible NOS-isoforms is increased in Alzheimer's disease, in APP23 transgenic mice and after experimental brain lesion in rat: evidence for an induction by amyloid pathology

The nitric oxide-synthesizing enzyme nitric oxide synthase (NOS) is present in the mammalian brain in three different isoforms, two constitutive enzym es (i.e., neuronal, nNOS, and endothelial eNOS) and one inducible enzyme (i NOS). All three isoforms are aberrantly expressed in Alzheimer's disease gi ving rise to elevated levels of nitric oxide apparently involved in the pat hogenesis of this disease by various different mechanisms including oxidati ve stress and activation of intracellular signalling mechanisms. It still i s a matter of debate, however, whether the abnormal expression of NOS isofo rms has some primary importance in the pathogenetic chain and might thus be a potential therapeutic target or only reflects a secondary effect that oc curs at more advanced stages of the disease process. To tackle this questio n, we analysed the expression of both eNOS and WOS in patients with sporadi c AD, in transgenic mice expressing human amyloid precursor protein (APP) w ith the Swedish double mutation under control of the Thy1 promotor (APP23 m ice), and after electrolytic cortical lesion in rat, an experimental paradi gm associated with elevated expression of APP. In all three conditions, an astrocytosis was induced accompanied by a strong increase of both iNOS and eNOS. Both NOS isoforms were frequently though not always colocalized. Thus , based on the expression pattern of NOS isoforms three types of astrocytes , expressing only one of the two isoforms or both together could be disting uished. In both AD and transgenic mice eNOS-expressing astrocytes exceeded iNOS-expressing astrocytes in number. Astrocytes with elevated levels of WO S or eNOS were constantly seen in direct association with A beta -deposits in AD and transgenic mice and were found in the vicinity of the lesion site in the rat cortex. The results of the present study show that expression o f both iNOS and eNOS is increased in activated astrocytes under experimenta l conditions associated with elevated expression of APP (electrolytic brain lesion) or A beta -deposition (APP23 transgenic mice). Therefore, it is su ggested that altered expression of these NOS isoforms being part of AD path ology is secondary to the amyloid pathology and might not be primarily invo lved in the pathogenetic chain though it might contribute to the maintenanc e, self-perpetuation and progression of the neurodegenerative process. (C) 2001 Published by Elsevier Science B.V.