Pharmacological and lesion models

Putative AD-like cognitive deficits are modeled in animals by producing electrolytic, mechanical, neurochemical, or immunotoxin lesions of the brain, predominantly the basal forebrain,12 a strategy based on the cholinergic hypothesis of AD. Cholinergic denervation produces attention and memory dysfunction in multiple preclinical test species. Scopolamine, a muscarinic ACh receptor (mAChR) antagonist, also produces cognitive dysfunction. Lesion of the basal forebrain and in particular the nucleus basalis magnocellularis (NBM) in the rat with the excitotoxic glutamate receptor agonists, ibotenate, quinolate, kainate, quisqualate, or AMPA, can model the cognitive deficits associated with AD. These excitotoxins are predominately axon sparing and cause neuronal death by an excessive influx of Ca2 +. Reactive gliosis is also observed in these models.

The specific cholinergic toxin, AF64 1, binds to the high-affinity choline uptake system, and also produces lesions in the brain. High-dose intracerebroventricular AF64 produces widespread damage across the brain, while low dose produces more damage selective to the NBM. Immunotoxins can also produce lesions using cell surface receptor expression of cholinergic neuron markers, e.g., the low-affinity nerve growth factor receptor p75NGF Saporin-conjugated antibodies injected intracerebroventricularly or into specific brain regions produce dose-dependent cholinergic neuron loss. To mimic AD pathophysiology more closely, infusion of fibrillar b-amyloid (A^42) into the NBM has also been employed, causing transient hypofunction of cholinergic neurons, i.e., function is restored when fibrils are cleared.

A major advantage of lesion models is that they produce a deficit in a short time span in readily accessible animals, i.e., rodents, providing the opportunity to evaluate NCEs rapidly. Deficits in attention and short-term memory resulting from cholinergic lesions can be measured postlesion using a variety of behavioral assays, e.g., delayed alternation in a T-maze or the Morris water maze. However, such cognitive deficits are of short duration and do not mimic the longer-term progressive dysfunction observed in AD. Also, the AD tombstones, plaques, and tangles are not observed, although an inflammatory response may occur.

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