Rodent Studies

Although no model faithfully recaptitulates the complex etiology and time-dependent loss of cholinergic neurons seen in AD patients, model systems have been developed to answer the specific question: Can NGF prevent the death of damaged cholinergic neurons following acute trauma? Initial studies determined whether encapsulated BHK cells modified to produce human NGF could prevent cholinergic neuron loss following aspiration of the fimbria/fornix (85) (Fig. 6). Rats received lesions of the fimbria/fornix followed by intraventricular implants of either NGF-producing or control (nontransfected) cells. Control-implanted animals had an extensive loss of ChAT-positive cholinergic neurons ipsilateral to the lesion that was prevented by NGF cell implants. Quantitation of ChAT-positive neurons for the 2 groups revealed that with the control capsules, 14% of the neurons remained viable on the lesioned side compared with the nonlesioned side, whereas with the NGF capsules, 88% of the cholinergic neurons were rescued.

One of the cardinal behavioral symptoms of AD is a progressive loss of cognitive ability. Just as no animal model faithfully mimics the complex etiology and pathophysiology of AD, comparable behavioral abnormalities are difficult to reproduce in animal models. However, the aged rodent shows a progressive degeneration of basal forebrain cholinergic neurons, together with marked cognitive impairments, which are partly reversible by administering NGF. Lindner et al. (67) trained 3-, 18-, and 24-month-old rats on a spatial learning task in a Morris water maze (Fig. 7). Cognitive function, as measured in this task, declined with age. Evidence of age-related atrophy of cholinergic neurons was observed in the striatum, medial septum, nucleus basalis, and vertical limb of the diagonal band. These anatomical changes were most se-

Figure 6 Scanning electron micrograph of a typical macrovoid-containing membrane used in cell encapsulation.

vere in animals with the greatest cognitive impairments, suggesting a link between the 2 pathological processes. Following training, animals received bilateral intraventricular implants of encapsulated NGF or control cells. The 18- and 24-month old animals receiving NGF cells showed a significant improvement in cognitive function (Fig. 7). No improvements or deleterious effects were observed in the young nonimpaired animals. Anatomically, the NGF released from the encapsulated cells increased the size of the atrophied basal forebrain and striatal cholinergic neurons to the size of the neurons in the young healthy rats. Furthermore, there was no evidence that the NGF cells produced changes in mortality, body weights, somatosensory thresholds, potential hyperalgesia, or activity levels, suggesting that the levels of NGF produced were neither toxic nor harmful to the aged rats.

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