Alzheimer’s, Parkinson’s, Epilepsy and Caloric Resrtiction & Aging
The photo-micrograph shown above is an example of the silver impregnation
method for detection of nerve cell degeneration. Dying nerve cells appear brown-black. Other cells are orange-yellow. This photo-micrograph shows a segment of the hippocampal CA1 region of a rat, 7 days after injection of kainate. Kainate injection models glutamatergic neurotoxicity, which is one of the processes underlying degeneration in several human neurological diseases.
Aging and neurodegenerative diseases: Alzheimer’s (AD), Parkinson’s (PD) and Epilepsy
Iron and oxidative stress
Several lines of evidence suggest contribution of oxidative stress to neurodegeneration in neurological diseases including Alzheimer’s and Parkinson’s disease. However, oxidative stress is a general principle. Such principle alone does not account for the differences in anatomical distribution of neurodegeneration between AD and PD. While in AD the anatomical distribution of neurodegeneration includes extensive parts of the cortex and hippocampus, in PD, the distribution of neurodegeneration includes the basal ganglia, mainly the substantia nigra pars compacta.
In search of a principle that may account for differential anatomical distributions in neurodegenerative diseases, I have focused on excitatory amino acids. Excitatory amino acids (EAAs) act as neurotransmitters in specific neural circuits in brain. In collaboration with Prof. Richard Ebstein, I have explored the effects of kainic acid (kainate), an analog of the excitatory amino acid glutamate (Shoham et al 1992, Shoham and Ebstein 1997). We have shown that kainate can induce neurodegenerative phenomena along anatomical pathways similar to those observed in AD. This finding provides evidence supporting a role for EAAs in AD.
One of the mechanisms of neurodegeneration activated by EAAs is oxidative stress. One of the factors that can augment oxidative stress is the distribution of iron in brain, since iron is a metal that readily donates electrons. In PD, iron accumulates in the substantia nigra pars compacta in the vicinity of degenerating dopaminergic neurons. Iron has been detected in “senile-“or “neuritic- plaques” and neurofibrillary tangles which are two major hallmarks of AD. Thus, circumstantial evidence supports a role for iron in both AD and PD neurodegeneration (Shoham and Youdim 2000).
To explore the relation between EAAs and iron accumulation, we have explored the distribution of iron following focal injection of excitatory amino acids into the brain (Shoham et al 1992). This study confirmed that iron accumulates along the pathways activated by focal injection of kainate.
To explore the causal role of such activation, in collaboration with Prof. Moussa Youdim of the Technion, we have tested the effect of low-iron diet on the degeneration that follows treatment with an excitatory amino acid analog – kainic acid. Low-iron diet attenuated the damage to hippocampus induced by kainic acid (Shoham and Youdim 2000, Shoham and Youdim 2004). This study is directly relevant to AD since the protection of hippocampus by low-iron diet implies that iron-chelating drugs might protect the hippocampus in AD. This study also is relevant to Temporal Lobe Epilepsy since kainic acid induces seizures similar to temporal lobe epilepsy.
Caloric restriction (CR) and oxidative stress
CR means reduction of daily caloric intake without reduction in essential micronutrients such as minerals and vitamins. CR is the only treatment that reliably extends life span in all organisms tested thus far. CR has been shown to attenuate oxidative stress and to attenuate aging-association accumulation of iron in brain. Thus, CR might be used as a way of protecting the brain from aging-associated neurodegenerative diseases (Shoham book chapters).
In addition, since reduction of daily caloric intake can affect psychological processes as seen in human anorexia nervosa, it is important to know how CR affects the function of brain regions involved in regulation of emotional responses (Shoham book chapters, Shoham et al 2000 with Berry).
Oxidative stress and damage to myelin: The Streptozotocin (STZ) model of AD
Streptozotocin is a toxin that has been known for a long time to induce diabetes in rats when injected peripherally. When injected into the cerebral ventricles it impairs glucose utilization in cortex and hippocampus.
This model is relevant to AD in light of evidence for impaired brain metabolism in this disease. The brain is highly dependent upon glucose as a source of energy and its oxidative metabolism plays an essential role in the maintenance of synaptic activity and cellular homeostasis. Glucose metabolism is reduced by 30-50% in the posterior cingulate, parietal and temporal regions of the cortex at an early stage of Alzheimer’s disease.
In collaboration with Prof. Marta Weinstock-Rosin of the Hebrew University in Jerusalem I have explored the anatomical distribution of pathology induced by STZ in rats (Weinstock et al 2001, Shoham et al 2003). Using silver impregnation staining we found that STZ caused damage to the fornix, specifically to myelinated axons. We were also able to identify inflammatory processes, reflected by gliosis, which were localized to the residual white matter of the fornix. STZ-treated rats showed impaired working memory in the Morris water maze a test of memory in rats. This test validates the model for AD. Understanding the mechanisms underlying the effects of STZ may lead to development of new treatments for AD.
Although the mechanism by which STZ damages myelin is not yet known, it could involve the induction of oxidative stress to which myelin is particularly vulnerable. Reactive oxygen species can be produced by microglia, which are activated by icv STZ. Understanding these mechanisms may help develop approaches to prevention of damage to myelin in several neurological disorders.