Characteristics of AD

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Alzheimer's disease (AD) is a progressive neurodegene-rative disorder that is characterized by the relentless decline of cognitive function, judgment, perception and personality, and ultimately the loss of the distinctive and shared qualities that define an individual's existence (Cummings, 2004). For unknown reasons, the full behavioral and neurodegenerative phenotype of AD is unique to humans, a characteristic that has hindered the development of representative AD models. However, in recent years substantial progress has been made in the development of animal models of behavioral and pathological components of AD.

Histopathologically, AD is characterized primarily by the presence of senile plaques and neurofibrillary tangles (NFTs) in specific brain regions (Figure 11.1) (see Hauw and Duyckaerts, 2001; Hardy and Selkoe, 2002 for review). Senile plaques are intricate lesions centered about a core of aggregated, fibrillar amyloid-p (Ap) peptide; neurofibrillary tangles are intracellular inclusions comprised of aberrant, microtubule-associated protein tau. A variety of additional pathologic changes accompany plaques and tangles in AD, including cerebral p-amyloid angiopathy (CAA; Figure 11.1B), granulovacuolar degeneration, inflammation, and loss of specific neurons and synapses (Hauw and Duyckaerts, 2001) (Cummings, 2004). NFTs occur in over 20 brain disorders besides AD, and mutations in the gene for tau on chromosome 17 have been linked to hereditary CNS tauopathies (FTDP-17) (Lee et al., 2001, 2005). Despite some similarities, the genetic tauopathies differ in important ways from AD, one being the critical role that Ap plays in Alzheimer pathogenesis.

Alzheimer's disease afflicts primarily the higher order processing regions of the cerebral cortex and associated subcortical nuclei. The pathogenic process begins stereotypically in the allocortex of the medial temporal lobe and progresses inexorably to other brain regions over the course of many years (Braak et al., 1997). Structures that are heavily involved in the end-stages of the disease are the neocortex, hippocampus, and amygdala, whereas some regions (such as the cerebellum) remain relatively spared (Hauw and Duyckaerts, 2001). Within affected areas, certain neurons are selectively vulnerable, in particular long projection neurons and/ or neurons that use glutamate, acetylcholine, gamma-amino butyric acid (GABA), dopamine, or norepineph-rine as neurotransmitters.

Paradoxically, in spite of evidence that Ap plays a primary role in the causation of AD (below), the atypical, intraneuronal accumulation of tau is the first lesion to appear in aging humans (Braak et al., 1997). Tau protein, which normally stabilizes cellular micro-tubules, begins to polymerize separately in affected cells,

Figure 11.1 The Canonical Pathology of Alzheimer's Disease. (A) Gallyas silver-stained section showing neurofibrillary tangles (arrows) and senile plaques (arrowheads) in the hippocampal formation of an AD patient (10X objective). (B) Ap-immunostained scction showing senile plaques (arrowhead) and CAA (grey arrow) in the neocortex (antibody 10D5; 20X objective).

Figure 11.1 The Canonical Pathology of Alzheimer's Disease. (A) Gallyas silver-stained section showing neurofibrillary tangles (arrows) and senile plaques (arrowheads) in the hippocampal formation of an AD patient (10X objective). (B) Ap-immunostained scction showing senile plaques (arrowhead) and CAA (grey arrow) in the neocortex (antibody 10D5; 20X objective).

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