Aging renders the brain vulnerable to amyloid β-protein neurotoxicity

Abstract

The formation of fibrillar deposits of amyloid beta protein (Abeta) in the brain is a pathological hallmark of Alzheimer's disease (AD). A central question is whether Abeta plays a direct role in the neurodegenerative process in AD. The involvement of Abeta in the neurodegenerative process is suggested by the neurotoxicity of the fibrillar form of Abeta in vitro. However, mice transgenic for the Abeta precursor protein that develop amyloid deposits in the brain do not show the degree of neuronal loss or tau phosphorylation found in AD. Here we show that microinjection of plaque-equivalent concentrations of fibrillar, but not soluble, Abeta in the aged rhesus monkey cerebral cortex results in profound neuronal loss, tau phosphorylation and microglial proliferation. Fibrillar Abeta at plaque-equivalent concentrations is not toxic in the young adult rhesus brain. Abeta toxicity in vivo is also highly species-specific; toxicity is greater in aged rhesus monkeys than in aged marmoset monkeys, and is not significant in aged rats. These results suggest that Abeta neurotoxicity in vivo is a pathological response of the aging brain, which is most pronounced in higher order primates. Thus, longevity may contribute to the unique susceptibility of humans to Alzheimer's disease by rendering the brain vulnerable to Abeta neurotoxicity.

Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer’s disease

“…The observation of a local microenvironment in which microglia are recruited and activated after plaque formation further supports a model in which plaques act as a reservoir of bioactive molecules ( Supplementary Fig. 7), which subsequently lead to neuronal alterations 19 including local loss of dendritic spines and axonal dystrophies 26 . These data thus lead to a model consistent with a prediction of the amyloid hypothesis in which amyloid deposition, activation and recruitment of microglia and local neuritic changes play out as a sequential cascade leading to neurodegeneration 1 .…”

“…In this third APP transgenic line, we Stokin et al recently proposed that amyloid deposits followed axonal trafficking defects, marked morphologically as neuritic dystrophies. In contrast, amyloid deposition has been postulated to cause neuronal alterations 1,19 . To study the temporal relation between newly formed plaques and dystrophic neurites, we compared the shape and trajectories of yellow fluorescent protein (YFP) fluorescent neurites before and after plaque formation in B6C3-YFP animals (Fig.…”

Substrate‐Bound β‐Amyloid Peptides Inhibit Cell Adhesion and Neurite Outgrowth in Primary Neuronal Cultures

“…Some of these studies found no effect of intracranial A␤ injections on neuronal cell loss (Podlisny et al, 1993;Winkler et al, 1994), whereas others found that injection of synthetic A␤ (Kowall et al, 1991) or brain plaque extracts (Frautschy et al, 1991) caused neuronal loss, gliosis, and a dystro-phic neuritic reaction. More recently, Geula et al (1998) reported that A␤ peptides are neurotoxic when injected into aged rhesus monkeys, but not in younger monkeys or aged rodents. This suggests that there is an age-and species-dependent susceptibility factor, which could interact with A␤ and influence its toxicity.…”

Isolation of the genomic clone of the rhesus monkey beta‐amyloid precursor protein

“…The regulatory region of the human BAPP gene was demonstrated to promote neuron-specific gene expression in the CNS of transgenic mice (16). The relevance of the rhesus monkey as an appropriate animal model for AD has recently been highlighted (26). Recently, conserved elements in the 5' regulatory region of the BAPP gene have been mapped in primates (27), though a detailed analysis of the BAPP gene promoter from a nonhuman primate has not been reported.…”