Alzheimer's disease: a review concerning immune response and microischemia.

Alzheimer's disease (AD), as we think of it today, is the idiopathic progressive loss of cognitive function over a period of several years. The risk of late onset dementia increases significantly with each decade of life such that half of the population over the age of 80 is vulnerable to this disease (1). We know that proper functioning of the central nervous system is dependent on adequate blood flow to remove harmful metabolic products and supply nutrients such as glucose and oxygen to the brain. It has been suggested that cerebral hypoperfusion causes AD (2). Mean cerebral blood flow decreases with age and with sclerosis of cerebral blood vessels. Blood flow appears to increase in stimulated areas of the brain during different activities. However, there is a derangement of blood flow in disease states; this has been documented in the temporal lobes of AD patients, (3,4). English language journal articles located by a MEDLINE search (1960-1999) were reviewed with consideration to the hypothesis that Alzheimer's disease is an autoimmune disease initiated by low oxygen tension and microischemia. Inflammation is thought to be a known contributor to the pathology of AD (5,6). Recent reports support the concept of autoimmunity as a final common pathway of neuron death, particularly for cholinergic in Alzheimer's disease (6). A model of Alzheimer's disease is proposed and related research and treatment modalities are discussed.

Cells containing immunoreactive estrogen receptor-alpha in the human basal forebrain.

The distribution of estrogen receptor protein-alpha (ER-alpha)-containing cells in the human hypothalamus and adjacent regions was studied using a monoclonal antibody (H222) raised against ER-alpha derived from MCF-7 human breast cancer cells. Reaction product was found in restricted populations of neurons and astrocyte-like cells. Neurons immunoreactive for ER-alpha were diffusely distributed within the basal forebrain and preoptic area, infundibular region, central hypothalamus, basal ganglia and amygdala. Immunoreactive astrocyte-like cells were noted within specific brain regions, including the lamina terminalis and subependymal peri-third-ventricular region. These data are consistent with the location of estrogen receptors in the basal forebrain of other species and the known effects of estrogens on the cellular functions of both neurons and supporting elements within the human hypothalamus and basal forebrain.

Somatostatin-gene expression in the postmortem adult and fetal human brain.

We have examined the utility of in situ hybridization for detecting pre-prosomatostatin mRNA in postmortem human brain. In preliminary studies, Northern blot analysis using a rat model, which simulates the normal pattern of human post-mortem brain cooling, revealed retention of significant amounts of hybridizable somatostatin mRNA relative to control levels between 12 and 24 hours after death. mRNA extracted from postmortem fetal human brain specimens showed hybridization to cRNA probes directed against pre-prosomatostatin mRNA. We thus undertook in situ hybridization studies. Antisense RNA probes were hybridized to neurons that expressed pre-prosomatostatin in 10-microns sections of adult and fetal human brain. The distribution of pre-prosomatostatin mRNA-containing neurons was similar to that observed for somatostatin-like immunoreactivity; however, the in situ hybridization technique was a more sensitive marker of neuronal perikarya. Our results indicate that hybridization to pre-prosomatostatin mRNA is a useful method for localizing these peptidergic neurons in postmortem human brain tissue.

Labeling of human retinohypothalamic tract with the carbocyanine dye, DiI.

The carbocyanine dye, DiI, was used to demonstrate human retinohypothalamic tract (RHT) projections in 6 normal human postmortem brains. In 5 of 6 brains, labeling was seen extending from the site of implantation in the distal optic nerve to both the ipsilateral and contralateral suprachiasmatic nuclei. This study confirms the presence of RHT projections in humans, and demonstrates the usefulness of DiI for neuronal tracing in human postmortem tissue.

Cytogenetic analysis of chromosome region 73AD of Drosophila melanogaster.

The 73AD salivary chromosome region of Drosophila melanogaster was subjected to mutational analysis in order to (1) generate a collection of chromosome breakpoints that would allow a correlation between the genetic, cytological and molecular maps of the region and (2) define the number and gross organization of complementation groups within this interval. Eighteen complementation groups were defined and mapped to the 73A2-73B7 region, which is comprised of 17 polytene bands. These complementation groups include the previously known scarlet (st), transformer (tra) and Dominant temperature-sensitive lethal-5 (DTS-5) genes, as well as 13 new recessive lethal complementation groups and one male and female sterile locus. One of the newly identified lethal complementation groups corresponds to the molecularly identified abl locus, and another gene is defined by mutant alleles that exhibit an interaction with the abl mutants. We also recovered several mutations in the 73C1-D1.2 interval, representing two lethal complementation groups, one new visible mutant, plucked (plk), and a previously known visible, dark body (db). There is no evidence of a complex of sex determination genes in the region near tra.