Konrad Beyreuther

Amyloid in the brains of aged squirrel monkeys

SummaryIn this immunocytochemical study, the brains of nine squirrel monkeys (Saimiri sciureus), ranging from 8 to 27 years of age, were examined for the presence and distribution of β/A4 amyloid, a 4-kilodalton peptide. In aged squirrel monkeys, amyloid is associated primarily with intracerebral and meningeal capillaries and arterioles and occurs to a lesser degree as small and/or diffuse deposits in the neural parenchyma and in the dense cores of senile plaques. Cerebrovascular amyloid is found primarily in neocortex, amygdala, and septum verum and is rare or nonexistent in other subcortical gray structures, white matter, cerebellum, and spinal cord; this pattern of localization is comparable to that in humans with cerebral amyloid angiopathy. There is a significant correlation between cerebrovascular and parenchymal deposits of amyloid. However, cerebrovascular amyloid is always the most abundant form in squirrel monkeys, even in cases of severe cerebral amyloidosis. In contrast to squirrel monkeys, aged rhesus monkeys (Macaca mulatta) develop, mostly parenchymal deposits of amyloid and have relatively less vascular amyloid. This species difference in the histological distribution of amyloid suggests that separate mechanisms may influence the accumulation of amyloid in cerebral blood vessels and in the neural parenchyma. These data also indicate that the squirrel monkey can serve as a model for investigations of cerebrovascular amyloidosis.

The transmembrane domain of the amyloid precursor protein in microsomal membranes is on both sides shorter than predicted.

The amyloid precursor protein is cleaved within its ectodomain by β-amyloid-converting enzyme (BACE) yielding C99, which is further cleaved by γ-secretase within its putative transmembrane domain (TMD). Because it is difficult to envisage how a protease may cleave within the membrane, alternative mechanisms have been proposed for γ-cleavage in which the TMD is shorter than predicted or positioned such that the γ-cleavage site is accessible to cytosolic proteases. Here, we have biochemically determined the length of the TMD of C99 in microsomal membranes. Using a single cysteine mutagenesis scan of C99 combined with cysteine modification with a membrane-impermeable labeling reagent, we identified which residues are accessible to modification and thus located outside of the membrane. We find that in endoplasmic reticulum-derived microsomes the TMD of C99 consists of 12 residues that span from residues 37 to 48, which is N- and C-terminally shorter than predicted. Thus, the γ-cleavage sites are positioned around the middle of the lipid bilayer and are unlikely to be accessible to cytosolic proteases. Moreover, the center of the TMD is positioned at the γ-cleavage site at residue 42. Our data are consistent with a model in which γ-secretase is a membrane protein that cleaves at the center of the membrane.

Role of Copper and Other Transition Metal Ions in the Pathogenesis of Parkinson’s Disease, Prion Diseases, Familial Amyotrophic Lateral Sclerosis, and Alzheimer’s Disease

During the last few years, there has been growing evidence based on experimental data that Cu and other transition metal ions may have important roles in the pathogenesis of a series of hereditary and sporadic disorders of the central nervous system (CNS). It is suggested that metal ions such as Cu exert toxicity during electron-transfer reactions and also play a structural role by changing the conformation of proteins upon specific binding. In contrast, Zn is assumed to play a purely structural role because it exists exclusively in one oxidation state. According to presently accumulating knowledge, Cu complexes are especially sensitive to redox reactions (in the form of “free”) -Cu ions in the Fenton-type reaction). On the other hand, copper is an essential element—being a cofactor of detoxifying enzymes such as of Cu/Zn-superoxide dismutase (SOD). According to the high-affinity binding of Cu to the native amyloid precursor protein (APP) and the prion protein (PrP), Cu is suggested to exert conformation stabilizing functions, to act as a redox active detoxifying cofactor, and is involved in metabolic transport (APP) or absorption-secretory (PrP and APP) functions. Currently, there are no data to confirm the hypothesis that an enhanced exogeneous exposure to Cu (or other transition metal ions) may accelerate the progression of neurodegenerative diseases or even to show a significant association with increased metal-ion levels in general, or what may occur with a higher frequency in response to exogenous exposure. In contrast, a causal relationship has been shown for neurodegenerative symptoms and chronic inhalatory exposure of Mn because of its unique ability to cross the blood-brain barrier via the olfactory epithelium.