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BOX 2, cont'd (B) In other studies, the interaction of Ap peptides with the a7nicotinic ACh receptor was assessed by ligand receptor binding assay using the a7nAChR-selective ligand alpha-bungarotoxin. (Left-hand panel) 125I-a-bungarotoxin (BTX) binding to a7 receptor-containing cell membranes was assessed. Amyloid beta peptide competes for bungarotoxin binding to the alpha-7 receptor with high affinity. (Right-hand panel) 125I-AP1-40 binding to a7 receptor-containing membrane was also assessed. Alpha-7 selective antagonists (BTX, MLA, and epibatidine) compete for 125I-AP1-40 binding with high affinity. Overall these data indicate a high-affinity interaction of amyloid beta peptide with the alpha7 nicotinic acetylcholine receptor. Mean data from at least three experiments are presented. Nonlinear regression data curve fit was performed by Prism. Reproduced from Wang et al. (89).

(Figure 1). Senile plaques exhibit several features. Plaque formation is associated with the accumulation of dystrophic neurites in the areas surrounding senile plaques. At the core of the senile plaque is a structure known as the amyloid plaque (10). An additional neuropathological feature of AD is neurofibrillary tangles (NFTs). Progression of the disease is marked by an increase in the number of amyloid plaques and neuro-fibrillary tangles in affected neurons and brain areas, accompanied ultimately by neuronal loss. In the next two sections, we will cover the molecular composition of NFTs and amyloid plaques. A number of the most important findings in the history of AD research were related to discovering the chemical nature of these materials.

FIGURE 1 Amyloid plaques and neurofibrillary tangles, the two principal neuropathologic markers for AD. A indicates an amyloid plaque and B indicates a neurofibrillary tangle. See text for additional discussion. Figure courtesy of Poul Jorgensen, Claus Bus, Niels Pallisgaard, Marianne Bryder, and Arne Lund Jorgensen.

FIGURE 1 Amyloid plaques and neurofibrillary tangles, the two principal neuropathologic markers for AD. A indicates an amyloid plaque and B indicates a neurofibrillary tangle. See text for additional discussion. Figure courtesy of Poul Jorgensen, Claus Bus, Niels Pallisgaard, Marianne Bryder, and Arne Lund Jorgensen.

Neurofibrillary Tangles

One of the principal cytopathological diagnostic features of AD is NFTs. NFTs are located in the soma, dendrites, and dystrophic neurites (abnormal neuronal processes and axon terminals) of affected neurons. NFTs comprise aggregates of poorly soluble filaments, the principal component being hyperphosphorylated isoforms of the microtubule-associated protein tau (see reference 16 for a review and Figure 1). Hyperphosphorylated tau from human AD tissue can be phospho-rylated at more than 20 different sites. Tau is a substrate for a variety of protein kinases including ERK and JNK MAP kinases, cyclin-dependent kinase 5 (cdk5) and Glycogen Synthase Kinase 3 (GSK3). The relevant kinases that phosphorylate tau in AD and other pathologic states are currently under investigation, but all these kinases are viable candidates for mediating increased tau phosphorylation in AD. Similarly, the basis for aberrant kinase activation (or aberrant phosphatase inhibition) in AD is an area of ongoing investigation.

Current hypotheses invoke the idea that hyperphosphorylation of tau has two effects. First, it causes dissociation of tau from the microtubule cytoskeleton and hence leads to cytoskeletal derangement. Second, hyperphosphorylated tau aggregates into a cytopathologic feature known as paired helical filaments (PHFs). These intracellular protein aggregates themselves may be cytotoxic, by mechanisms yet to be discerned (see reference 17 for a review). Thus, the combination of architectural derangement and neuronal inclusions is hypothesized to lead to both neuronal dysfunction and ultimately neuron death. It should not escape our attention that we discussed many of the identified tau kinases in Chapters 6 and 7 in terms of their involvement in synaptic plasticity and memory formation.

The neurofibrillary tangle is a cytopatho-logical feature associated with several neuropathological disorders besides AD, such as amyotrophic lateral sclerosis/ Parkinsonism dementia complex, Pick's disease, corticobasal degeneration, and progressive supranuclear palsy. This spectrum of disorders is now known as the "Tauopathies" (17). It is likely that NFTs are a hallmark of neurodegeneration; however, as mentioned previously, the causative role that hyperphosphorylated tau and NFTs play in neurodegeneration is not well understood.

Amyloid Plaques

Senile plaques are composed of dystrophic neurites displayed around extracellular deposits of amyloid. A key breakthrough, and perhaps the key breakthrough, in understanding the molecular pathology of AD came with the identification of the chemical structure of amyloid by George Glenner in 1984 (18). This work along with subsequent studies (19) made clear that AD-associated amyloid in both the vascular system and in amyloid plaques is comprised of aggregates of a peptide termed amyloid beta (Ap) peptide.

"Amyloid beta peptide" is actually a mixture of peptides in vivo. Ap comprises peptides with a length of 40 to 43 amino acids, all of which are identical except for the carboxy-terminal 3 amino acids. The sequence of the longest (43 amino acid) peptide is

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