Faculty Bibliography

We have observed that single amyloid-beta 25-35 (A beta) injections (5.0 nmol) into the right amygdala of rats produce progressive cytoskeletal and astrogliotic reactions not only within the amygdala, but also in distal brain regions that project to the amygdala. To determine if these effects are potentiated by bilateral injections, we injected A beta (5.0 nmol) into the left and right amygdala of young male Fischer rats. Animals were sacrificed 32 days postoperatively. Bilateral infusions of A beta induced significant neuronal shrinkage, tau-2 neuronal staining, and reactive astrocytosis within the right amygdala and/or hippocampus, compared with vehicle-treated rats. Surprisingly, the same brain regions within the left hemisphere were significantly less affected even though no differences were observed between the left and right amygdala in the size of Congored-positive A beta deposits. Unilateral injections of A beta into the left amygdala led to significant histological changes in the right amygdala and hippocampus, but not in the same brain regions within the left hemisphere. These results suggest a laterality in the histopathological effects of A beta in male Fischer rats. Identification of the cause for the lateralized effect of A beta may prove valuable for understanding the etiology of Alzheimer disease and provide possible therapeutic strategies designed to slow the progression of the disease

To determine if amyloid-beta (A beta) induces tau-immunoreactivity (IR) and reactive astrocytosis in vivo, we injected A beta 25-35 (5.0 nmol) into the right amygdala of rats. At 8 days postinjection, the peptide induced tau-2 IR in neuronal cell bodies and processes ipsilaterally in the amygdala, cingulate cortex, and hippocampus. At 32 days postinjection, the intensity of tau-2 IR was greater than at 8 days in the amygdala and hippocampus, but not in the cingulate cortex. Induction of Alz-50 IR also was progressive but the morphology and distribution was different from tau-2 IR. Beaded fibers with occasional neuronal perikarya were visualized with Alz-50, and the IR was primarily observed in the ipsilateral amygdala. In addition, amygdaloid injections of A beta 25-35 induced reactive astrocytosis, particularly in the ipsilateral hippocampus at 32 days postoperatively. To our knowledge, this is the first study to show that in vivo injections of A beta 25-35 induce progressive transsynaptic cytoskeletal and astrogliotic reactions, that gradually spread from the area of injection to brain regions that have prominent efferent connections with that area. These findings also suggest a direct association between plaque and tangle formation in Alzheimer's disease

beta-Amyloid peptides have been shown to potentiate the neurotoxic effect of excitatory amino acids in vitro. In order to determine if this occurs in vivo, four experiments were performed. We injected beta-amyloid 25-35 (beta A 25-35) and/or quinolinic acid (QA) bilaterally into the ventral pallidum/substantia innominata (VP/SI) of rats. Control rats received vehicle infusions. A high dose of QA (75.0 nmol/3 microliters) increased open field activity and impaired spatial learning in the Morris water maze, but did not affect the acquisition of a one-way conditioned avoidance response. These changes were associated with histological evidence of neurotoxicity and a reduction in amygdaloid but not frontal cortical or hippocampal choline acetyltransferase (ChAT) activity. A lower dose of QA (37.5 nmol/3 microliters) produced no behavioral effects. It reduced amygdaloid ChAT activity to a lesser extent than the higher dose (15% vs. 29-37%), and caused less histological damage. beta A 25-35 (1.0 or 8.0 nmol/3 microliters) failed to produce behavioral, histological or neurochemical signs of toxicity. Neither dose of beta A 25-35 potentiated the effects of QA (37.5 nmol) on behavior or amygdaloid ChAT activity, and did not appear to increase the histological damage caused by QA. These results suggest that in vivo beta A 25-35 is not neurotoxic and does not potentiate the neurotoxicity of QA in the VP/SI. Further, the histological effects of a high dose of beta A 25-35 (8.0 nmol/3 microliters; a cavitation containing a Congo red positive proteinaceous material) are quite distinct from those produced by a high dose of QA (75.0 nmol/3 microliters; widespread neuronal loss and gliosis)