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.

Recent observations in our laboratory have indicated substantial and systematic regional variations in the loss of cortical cholinergic fibers in Alzheimer disease (AD). Previous attempts to study the relationship between cortical cholinergic loss and the density of cortical pathological lesions have resulted in conflicting findings. Furthermore, most reports have correlated density of plaques and tangles with the residual level of cholinergic innervation rather than its loss. The purpose of the present study was to determine the relationship between loss of cholinergic axons and density of tangles and beta-amyloid (Abeta) deposits in various cortical areas of AD brains. Abeta deposits and tangles were observed throughout the cerebral cortex. Quantitative analysis revealed almost no correlation between loss of cholinergic fibers and the density of Abeta deposits. Qualitative observations revealed similar results when cored and neuritic plaques were considered separately. By contrast, cholinergic fiber loss displayed a significant correlation with the density of tangles (r = 0.52-0.79). However, in a few areas, such as the cingulate cortex, tangle density appeared to be unrelated to the loss of cholinergic fibers. These results indicate that cortical cholinergic denervation in AD is related to cytoskeletal pathology. However, the lack of a perfect relationship with cytoskeletal pathology implicates additional factors in the cholinergic pathology of AD.

Patients who suffer from Alzheimer's disease (AD) and a sub-population of community-dwelling elders show an exaggerated pupillary reaction to dilute tropicamide, a cholinergic antagonist. This finding may serve as an early diagnostic marker of AD. Here we report a likely pathological basis for this hypersensitive pupillary response. Our observations indicate that the Edinger-Westphal nucleus (EW), a known center for the control of pupillary function, is a selective target of Alzheimer pathology early in the course of the disease. In all AD cases examined, the EW contained plaques and tangles. In contrast, the adjacent somatic portion of the oculomotor complex was virtually spared of pathology. Early pathology in the EW is likely to initiate a cascade of events that may give rise to pupillary hypersensitivity.

We previously reported that alpha-motor neurons in organotypic cultures of rat spinal cord (OTC-SC) are resistant to excitotoxicity induced through NMDA receptors. Here we describe the effects of non-NMDA glutamate receptor agonists kainic acid (KA) and quisqualic acid (QUIS) on motor neurons in OTC-SC. Large ventral horn acetylcholinesterase-positive neurons (VHANs), most of which are motor neurons, were quite sensitive to QUIS and KA toxicity and displayed losses of 95% and 94%, respectively. Small VHANs were reduced by 41% and 61% only. Identical results were obtained in cultures stained for non-phosphorylated neurofilaments. These observations demonstrate that alpha-motor neurons are considerably more sensitive to KA and QUIS than to NMDA toxicity. The proposed excitotoxic mechanism of ALS, therefore, is most likely mediated through non-NMDA glutamate receptors.

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Neurotoxic effects of excitatory amino acid (EAA) receptor agonist N-methyl-D-aspartic acid (NMDA) and its antagonists on ventral horn cholinergic neurons were studied in organotypic rollertube cultures of spinal cord (OTC-SCs) using biochemical assays of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activity, and AChE histochemistry. NMDA exposure decreased ChAT and AChE activity by 83% and 66%, respectively. Cultures treated with NMDA also showed a marked loss of AChE staining in both dorsal and ventral horns and a significant, dose-dependent decrease in the number of ventral horn AChE-positive neurons (VHANs). NMDA treatment primarily resulted in the loss of small VHANs (< 300 microns2). VHANs with a size and distribution typical of alpha-motoneurons were relatively well preserved. The effects of NMDA on OTC-SCs appeared to be independent of the age of the cultures. The NMDA antagonist DL-AP5 completely prevented the NMDA-induced loss of ChAT activity, but only attenuated the effect of NMDA on ChE activity. The antagonists DL-AP5, D-AP5 and MK-801, used alone, caused significant loss and/or shrinkage of VHANs. These effects appeared to be distinct from the NMDA mediated toxicity. The results indicate that NMDA and its antagonists exert powerful toxic effects on ventral horn cholinergic neurons. The large cholinergic alpha-motoneurons, however, appear to be relatively immune to these toxic effects.

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