Aberrant expression of nNOS in pyramidal neurons in Alzheimer's disease ishighly co-localized with p21(ras) and p16(INK4a)

Aberrancies of growth and proliferation-regulating mechanisms might be crit ically involved in the processes of neurodegeneration in Alzheimer's diseas e (AD). Expression of p21ras and further downstream signalling elements inv olved in regulation of proliferation and differentiation as, for example, M EK, ERK1/2, cyclins, cyclin-dependent kinases and their inhibitors such as those of the p16(INK4a) family, are elevated early during the course of neu rodegeneration. Activation of p21ras can also directly be triggered by nitr ic oxide (NO), synthesized in the brain by various isoforms of nitric oxide synthase (NOS) that might be differentially involved into the pathomechani sm of AD. To study the potential link of NO and critical regulators of cell ular proliferation and differentiation in the process of neurofibrillary de generation, we analyzed the expression pattern of NOS-isoforms, p21ras and p16(INK4a) compared to neurofibrillary degeneration in AD. Additionally to its expression in a subtype of cortical interneurons that contain the nNOS- isoform also in normal brain, nNOS was detected in pyramidal neurons contai ning neurofibrillary tangles or were even unaffected by neurofibrillary deg eneration. Expression of nNOS in these neurons was highly co-localized with p21ras and p16(INK4a). Because endogenous NO can activate p21ras in the sa me cell which in turn leads to cellular activation and stimulation of NOS e xpression [H.M. Lander, J.S. Ogiste, S.F.A. Pearce, R. Levi, A. Novogrodsky , Nitric oxide-stimulated guanine nucleotide exchange on p21 ras, J. Biol. Chem. 270 (1995) 7017-7020], the high level of co-expression of NOS and p21 ras in neurons vulnerable to neurofibrillary degeneration early in the cour se of AD thus provides the basis for an autocrine feedback mechanism that m ight exacerbate the progression of neurodegeneration in a self-propagating manner. (C) 2000 Elsevier Science B.V. All rights reserved.