Neuropathological and genetic changes

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As specific markers of AD have not so far been identified before postmortem investigations have been undertaken, the accurate diagnosis can only be made retrospectively. However, even then no single neuropatho-logical lesion is definitive and the presence of multiple lesions, their density relative to the age of the patient and the absence of lesions characteristic of other types of dementia are essential for an accurate diagnosis. A gross decrease in brain weight and changes in gross brain structure (widening of the sulci and significant subcortical atrophy), while present to a greater extent than in elderly control subjects, are not considered to be specific for AD. However, atrophy of the cortex with a significant cell loss (40%+) together with a cell loss from subcortical structures such as the main cholinergic nuclei (the nucleus basalis of Meynert) are significantly correlated both with the major symptoms of dementia and with the cognitive deficits.

Neuronal loss and degeneration are associated with a significant decrease in markers of synaptic density. Thus the synaptophysin immunoreactivity in the frontal and parietal cortices and hippocampus is one of the strongest markers of the severity of dementia in AD. Such changes reflect neuronal degeneration but also the loss of presynaptic terminals together with the loss of neuropeptide and monoamine containing vesicles. The most prominent lesions associated with AD are the neuritic plaques (NPs) and the neurofibrillary tangles (NFTs) but it must be emphasized that these structures are not exclusively associated with AD as they frequently occur not only in elderly persons with normal brain function but also in other types of neurodegenerative disease.

NPs are extracellular protein deposits of varying size containing a core of amyloid beta peptide (Ab) together with neuritic inclusions. Ab is a 40-43 amino acid peptide formed from an amyloid precursor protein (APP) by two cleavage steps. The secretases (termed alpha, beta and gamma) are the enzymes involved in the cleavage of APP; gamma secretase is the enzyme primarily involved in the formation of Ab. There is evidence that presenilin-1 may be an essential component in the action of gamma secretase (Figure 14.4).

Evidence linking the abnormal breakdown of APP to the pathogenesis of AD has been provided by mutations of the APP gene and also the gene encoding the presenilins-1 and 2, these abnormalities inevitably being associated with AD. Furthermore, studies in transgenic mice have demonstrated that the introduction of such mutations leads to the deposition of Ab plaques that are associated with the memory deficits in the animals. With regard to the relationship between the accumulation of Ab and AD, it is now apparent that the increase in the density of NPs and Ab immunoreactivity that occurs even in the mildest cases of the disease are important; these changes are reported to occur before the patients meet the threshold criteria for the definitive diagnosis of the disease.

Insoluble clusters of misfolded (''sticky'') proteins are a common feature of AD and related dementias but the link between the accumulation of such proteins and the symptoms of the disease has been uncertain. Recently, however, Walsh and coworkers have suggested that such protein aggregates are inherently neurotoxic. These investigators have shown that whereas natural proteins adopt a characteristic three-dimensional structure on the basis of their amino acid composition with the hydrophobic residues being hidden within the molecule, in some cases these groups are exposed on the surface of the protein where they assemble into insoluble aggregates. On reaching a certain size they become the Ab plaques seen in AD. However, it has long been established that the symptoms of dementia in AD do not correlate with the density of amyloid plaques but do correlate with the quantity of the soluble, neurotoxic form of Ab. Experimental studies have now shown that it is this form of Ab that inhibits long-term potentiation, the molecular basis of memory formation, in the hippocampus.

NFTs are the second most important pathological feature of AD. These consist of paired helical filaments that are abnormal aggregates of abnormally folded, or hyperphosphorylated, forms of the microtubule associated tau protein. The progressive increase in the distribution of NFTs throughout many regions of the brain is related to the stages in the development of the disease. Thus the NFTs first appear in the entorhinal

Figure 14.4. Processing of amyloid precursor protein (APP) by the secretase enzymes. It would appear that y-secretase is primarily important for the formation of /î-amyloid.

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