Lesons of the cholinergic nucleus basalls of Meynert elevate the ex Wivo synthesis of ( amyloid precursor protein (f-APP) In the cerebral cortex, a major projection region. We have found that this elevation is reflc by Icased levels of f-APP mRNA. The induction is rapid (occurring 60 min after placement of the lsion) and perstent (remaning for at least 45 days after esloning (-APP in that numerous other proteins, including glial fibrillary acidic protein, were not affected.We have now characterized this lesion-induced (-APP expression more completely and report that (i) the elevated ex vivo synthesis is due to increased levels of(3-APP mRNA; (ii) the (-APP response to the lesion is rapid (exhibited within 60 min of lesioning) and persistent (remaining as long as 45 days post-lesion); (iii) the induction is reversible, requiring the attenuation of neurotransmitter release but not the loss of the subcortical neurons; (iv) subcortical lesions of the cortically projecting noradrenergic and serotonergic systems similarly induce cortical (-APP expression; and, finally, (v) other general perturbations of central nervous system function fail to induce the elevated (-APP synthesis response. These results suggest a cause and effect relationship between lesioninduced neurotransmitter deficits and (-APP induction, providing a possible linkage between subcortical neurotransmitter system deficits and amyloid deposition in the AD brain. METHODSPlacement of Lesions. Adult (-8 weeks old) male SpragueDawley rats (t225-250 g) purchased from Charles River Breeding Laboratories were subcortically lesioned at the following sites: (i) unilateral lesions of the nbM with N-methyl-D-aspartate (NMDA, 50 nM) as the excitotoxin as described (3); (ii) unilateral lesions of the ascending noradrenergic bundle (ANB) with 6-hydroxydopamine (2 p1 of a 4 iLg/ml solution) as described (4); (iii) dorsal raphe nucleus (DRN) lesions with 5,7-dihydroxytryptamine (50 mM) as described (5). Controls for the nbM and ANB lesions were the contralateral cortices, whereas controls for the DRN lesions were sham-operated animals. This latter shamoperated group also served as controls for any nonspecific contralateral effects produced by the unilateral nbM and ANB lesions.TransIent Inhibition of Corticl Acetylchoine (ACh) Release. A total of 12 male Long Evans hooded rats (300-325 g) was used in this experiment. Each rat was anesthetized with chloral hydrate (400 mg/kg, i.p.) and was positioned in a Kopfstereotaxic apparatus. A 28-gauge cannula was lowered into the region of the nbM (Bregma -0.5, ±3.0, -7.7). One-half of the rats were randomly assigned to group I and also received a 2-mm microdialysis probe (CMA/12; Bioanalytical Systems, West Lafayette, IN) that was stereotaxically directed at the frontal cortex at coordinates Bregma
Sixty-four Sprague-Dawley rats received ibotenic-acid-induced unilateral nucleus basalis of Meynert (nbM) lesions; 10 additional animals served as sham controls. Eight to ten days later, subjects with lesions received either fetal cholinergic transplants implanted within the ipsilateral (relative to the lesion) frontal cortex or control transplant surgeries. Lesioned animals with and without transplants were then treated with GM1 (20 mg/kg, i.p.) for either 0,1 or 10 days and were then trained and tested for 72-hour retention of passive avoidance. Results indicated that the lesion produced a significant impairment on this task. Transplant therapy combined with GM1 for 10 days yielded a significant reversal of this deficit. GM1 injections continued once per week for 4 weeks for half the lesioned animals in the transplant and no-transplant 10-day conditions. During a 6-month period, all subjects were assessed on two additional memory tasks (complex spatial discrimination and delayed spatial alternation). In general, there was no indication of a lesion, transplant, GM1, or transplant × GM1 effect on these tasks. Approximately 7.5 months after transplants, subjects were sacrificed and their frontal cortices examined for choline acetyltransferase (CAT) and acetylcholinesterase (AChE) activity. Only lesioned subjects with transplants which were given sustained GMl treatment (i.e., 10 days plus weekly injections for 4 weeks) showed significant attenuations of lesion-induced CAT and AChE depletions. These data suggest that a combined treatment strategy of fetal transplant plus GM1 is capable of reversing nbM lesion-induced memory and neurochemical deficits in an animal model of the cholinergic deficits in Alzheimer's disease.
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