Faculty Bibliography

The major neuropathological lesions defining Alzheimer's disease (AD) include neurofibrillary tangles and amyloid plaques, which are mainly composed of abnormally phosphorylated tau and amyloid-beta (A beta), respectively. Numerous neuropathological and neuroimaging studies indicate that at least one-third of AD cases are complicated by some degree of vascular pathology, whereas in a similar proportion of patients clinically diagnosed with vascular dementia, AD pathology is also present. Many classical vascular risk factors such as hypertension, diabetes mellitus, and hypercholesterolemia have recently been shown also to increase the risk of AD. Growing evidence suggests that vascular pathology lowers the threshold for the clinical presentation of dementia at a given level of AD-related pathology and potentially directly promotes AD lesions such as A beta plaques. Cerebral ischemia, chronically up-regulates expression of the amyloid precursor protein (APP), which is the precursor to the amyloid beta peptide and damages the blood-brain barrier (BBB), affecting A beta peptide clearance from the brain. Recognition of the importance of these vascular risk factors for AD-related dementia and their treatment will be beneficial not only for preventing cardiac, cerebral, and peripheral complications of vascular disease, but also will likely have a direct impact on the occurrence of sporadic AD in older subjects. In this paper, we review some of the links between vascular risk factors and AD pathology and present data on the direct effect of ischemia on cognitive function and A beta deposition in a mouse model of AD

Neurodegenerative disorders are becoming increasingly common and an ever greater healthcare burden, as the average age in Western populations rises. Many of these are conformational disorders, which are characterized by the accumulation of a host protein that undergoes a structural change increasing its beta-sheet content, rendering it toxic. The most common of these illnesses is Alzheimer's disease. Prion diseases are also conformational disorders, which are currently less common than Alzheimer's disease, however, these illnesses have no treatment and are universally rapidly fatal. The emergence of new variant Creutzfeldt-Jakob disease has raised the possibility of a large population at risk for this illness, as well as causing great concern regarding the safety of blood bank supplies. Recently, immune modulation has emerged as a highly promising therapeutic strategy for both Alzheimer's and prion diseases. We and others have demonstrated in both Alzheimer's and prion disease animal models that vaccination can dramatically improve the course of the illness. A human trial of an Alzheimer's disease vaccine using A beta1-42 was halted due to toxicity in a minority of patients (6%). However, recent data suggests that patients with a humoral response to A beta benefited cognitively from the vaccine. Toxicity in this human trial has been linked to excessive cell-mediated immunity. Novel vaccine strategies are under development for both Alzheimer's disease and prionoses which are predicted to have few or no significant side effects, while being efficacious. $$:

In Alzheimer disease (AD) patients, early memory dysfunction is associated with glucose hypometabolism and neuronal loss in the hippocampus. Double transgenic (Tg) mice co-expressing the M146L presenilin 1 (PS1) and K670N/M671L, the double 'Swedish' amyloid precursor protein (APP) mutations, are a model of AD amyloid-beta deposition (Abeta) that exhibits earlier and more profound impairments of working memory and learning than single APP mutant mice. In this study we compared performance on spatial memory tests, regional glucose metabolism, Abeta deposition, and neuronal loss in APP/PS1, PS1, and non-Tg (nTg) mice. At the age of 2 months no significant morphological and metabolic differences were detected between 3 studied genotypes. By 8 months, however, APP/PS1 mice developed selective impairment of spatial memory, which was significantly worse at 22 months and was accompanied by reduced glucose utilization in the hippocampus and a 35.8% dropout of neurons in the CA1 region. PS1 mice exhibited a similar degree of neuronal loss in CA1 but minimal memory deficit and no impairment of glucose utilization compared to nTg mice. Deficits in 22 month APP/PS1 mice were accompanied by a substantially elevated Abeta load, which rose from 2.5% +/- 0.4% at 8 months to 17.4% +/- 4.6%. These findings implicate Abeta or APP in the behavioral and metabolic impairments in APP/PS1 mice and the failure to compensate functionally for PS1-related hippocampal cell loss