Neuropathology

At postmortem, the brain in AD is lighter than aged-unaffected controls with more prominent sulci and a larger ventricular volume. Microscopic examination reveals the most prominent lesions described by Alzheimer—the extracellular plaque and intracellular neurofibrillary tangle. (26> No consensus has developed regarding which of these lesions is responsible for the cognitive impairment of AD. Plaques, or more precisely amyloid load, might correlate with the degree of cognitive impairment, (33) although a significant amyloid deposition is also found in normal, unimpaired, aged individuals. (34> However, there is a high degree of correlation between dementia severity and neurofibrillary tangle formation, (35> although it is possible that some of the features of AD are more stable than others; for example, extracellular neurofibrillary tangles persist after the neurone has died, whereas extracellular Lewy bodies are not found.

The plaque consists of an amyloid core surrounded by dystrophic neurites, which are themselves filled with highly phosphorylated tau protein. Studies of Down syndrome brains have suggested a temporal course to plaque formation. First, peptides derived from the amyloid precursor protein ( APP) are deposited in a diffuse plaque.(36) Over time this becomes organized as the amyloid peptides become fibrillar and form the amyloid deposit, neuritic change then occurs, and the plaque becomes fully mature.

Neurofibrillary tangles are composed of paired helical filaments, structures which are also found in the dystrophic neurites around mature plaques, and together with straight filaments, in neuropil threads. These filaments are themselves composed of the microtubule-associated protein, tau, which is present in a stably and highly phosphorylated state.(37) Tau is a neuronal-specific protein, found predominantly in the axon, that functions to stabilize microtubules, a property that is regulated by phosphorylation. Phosphorylated tau is less effective in promoting tubulin polymerization into microtubules, and in cells highly phosphorylated tau does not stabilize microtubules/38» In normal adult brain a proportion of tau is highly phosphorylated, but this proportion is considerably greater in AD. Tau deposits are a feature of other disorders, such as progressive supranuclear palsy and some frontotemporal degenerations. Mutations have been found in frontotemporal degenerations with parkinsonism (FTDP-17),(39> and progressive supranuclear palsy has also been associated with changes in the tau gene (40) thereby emphasizing the importance of this molecule to neurodegeneration.

Braak and Braak(4!> studied large numbers of brains from individuals who died at various ages and at different stages of dementia severity, which has resulted in the wide acceptance of the neuropathological staging of AD. The very earliest stages, before the clinical manifestation of dementia, are characterized by the appearance of highly phosphorylated tau in the hippocampus. In later stages, neurofibrillary tangles appear in the same brain regions and then become more widely distributed.

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