Superoxide Dismutase SOD1, Encoded on Chromosome 21, but Not SOD2 Is Overexpressed in Brains of Patients With Down Syndrome :

Neuropathologic confirmation is required to validate the NINCDS-ADRDA Work Group criteria for the clinical diagnosis of Alzheimer's disease (AD). Neuropathologic inclusion and exclusion criteria for AD, however, are not uniform. The purpose of this investigation was to examine the confirmation rate for the Work Group criteria against differing neuropathologic criteria for AD. The sample consisted of 57 cases, 22 of which had received a clinical diagnosis of AD. Nine neuropathologic criteria for AD were applied in a blind fashion to each of the 57 cases. Our results indicated that, depending on the neuropathologic criteria applied, the clinicopathologic agreement ranged from 64% to 86%. These findings demonstrate the need for universally accepted neuropathologic and clinical criteria for AD.

Copper/zinc superoxide dismutase (CuZn-SOD) is a key enzyme in the metabolism of oxygen free radicals. The gene encoding CuZn-SOD resides on human chromosome 21 and is overexpressed in Down syndrome (DS) patients. Overexpression of CuZn-SOD in transgenic (Tg) mice and cultured cells creates chronic oxidative stress leading to enhanced susceptibility to degeneration and apoptotic cell death. We have now found that three lines of Tg-CuZn-SOD mice, one of which also overexpresses S100beta, a glial calcium binding protein, are deficient in spatial memory. Furthermore, hippocampal slices taken from these mice have an apparently normal synaptic physiology, but are impaired in the ability to express long-term potentiation (LTP). This effect on hippocampal LTP was abrogated by treatment of slices with the H2O2 scavenger catalase or the antioxidant N-t-butyl-phenylnitrone (BPN). It is proposed that elevated CuZnSOD causes an increase in tetanic stimulation-evoked formation of H2O2 which leads to diminished LTP and cognitive deficits in these mice.

Synaptosomal associated protein 25 kDa (snap-25) is a widely distributed membrane-associated protein in the brain, mainly localized in nerve terminals. In nerve terminals, snap-25 participates in docking and/or fusion of synaptic vesicles with the plasmalemma, a process essential for synaptic vesicle exocytosis. Recent work suggests a role in brain development, forming presynaptic sites by regulating axonal outgrowth and nerve growth-induced neurite elongation. In Down syndrome (DS) brain, it is abnormally developed from early life, and brain pathology becomes even more pronounced when Alzheimer's disease (AD) develops in the fourth decade. This information led us to examine snap-25 in the brain of patients with DS and AD. We studied snap-25 and glial fibrillary acidic protein (GFAP) brain levels in five individual brain areas of 9 aged patients with DS, 9 patients with AD and 9 controls, applying two-dimensional gel electrophoresis. Decreased snap-25 levels were found in the five brain regions of the patients with DS and AD. Increased expression levels of GFAP were found in the frontal, parietal, temporal and occipital cortex regions of the DS and AD patients. Decreased snap-25 protein levels in the brain of DS and AD may reflect impaired synaptogenesis or represent neuronal loss. Findings of increased GFAP, a marker for neuronal loss, along with data from literature would support the notion of decreased snap-25 secondary to neuronal decay in both neurodegenerative disorders.