Neuropathology and Biochemistry of AD

The clinical manifestations of AD stem from abnormalities occurring among populations of neurons in neural systems/brain regions essential for memory, learning, and cognitive performance. Damaged circuits include the basal forebrain cholinergic system, amygdala, hippocampus, entorhinal and limbic cortex, and neocortex (White-house etal. 1982;Coyle etal. 1983; Braak and Braak 1994; Hyman etal. 1984; Markesbery et al. 2006; Petersen et al. 2006; Jicha et al. 2006; Braak and Braak 1991). In arecent study

(Markesbery et al. 2006), the character, abundance and distribution of the lesions (i.e., diffuse plaques, neuritic plaques, and tangles) were correlated with clinical signs in several cognitively characterized cohorts: controls and individuals with aMCI or eAD. There were no differences in the number of diffuse plaques between subject groups. In aMCI, tangles were significantly increased in the ventral medial temporal lobe regions as compared to controls; individuals with eAD showed greater numbers of NFT and neuritic plaques in both frontal lobes and temporal regions. Individuals with aMCI exhibited increased numbers ofneuritic plaques in neocortical regions as compared to controls, but not as compared to cases of eAD. Memory deficits appeared to correlate most closely with an abundance of NFT in CA1 of the hippocampus and in the en-torhinal cortex, leading the authors to conclude that tangles were more important than amyloid deposition in the progression from normal to MCI to eAD and that tangles in the medial temporal lobe play a key role in the memory declines in aMCI (Markesbery et al. 2006). Other studies (Petersen et al. 2006; Jicha et al. 2006) demonstrated that the majority of patients with MCI did not meet neuropathological criteria for AD; the data were interpreted to indicate that this syndrome reflected a transitional state in the evolution of AD. Because the regional distributions of NFT correlated most closely with the degree of clinical impairments from aged healthy controls to individuals with aMCI to cases of AD, the spread of NFT beyond the medial temporal lobe is thought to be linked to the development of dementia.

Cellular abnormalities within these neural circuits include the presence within neurons of conformationally altered isoforms of tau in the PHF comprising NFT, neurites, and neuropil threads (Lee et al. 2001; Goedert and Spillantini 2006), the presence of a variety of axonal pathologies, including varicosities and terminal clubs (also observed in aged, memory impaired Rhesus with Ap deposits; Kitt et al. 1984,1985; Martin et al. 1994; Selkoe et al. 1987; Stokin et al. 2005) an abundance of Ap-containing neuritic plaques (sites of synaptic disconnection) in regions receiving inputs from these populations of neurons, decrements in generic and transmitter-specific synaptic markers in the target fields of these cells (Whitehouse et al. 1982; Coyle et al. 1983; Sze et al. 1997), local astroglial and microglial responses, particularly associated with plaques, and evidence of death of neurons, possibly by apoptosis. Thus, the clinical manifestation ofaMCI and AD reflects disruption ofsynaptic communication in subsets of neural circuits associated with degeneration of axon terminals and, later, death of neurons in the brain (Whitehouse et al. 1982; Coyle et al. 1983; Braak and Braak 1991, 1994; Hyman et al. 1984).

In one hypothetical model thar mechanistically links Ap and phosphorylated tau, Ap42 species liberated at terminals oligomerize to form Ap assemblies or Ap-derived diffusible ligands (ADDLs), leading to synaptic damage (Wong et al. 2002,2005; Selkoe et al. 2002). Subsequently, a retrograde signal (of unknown nature), which originates at terminals, triggers the activation of kinases (or the inhibition of phosphatases) in the cell body. Phosphorylation of tau at certain serine and threonine residues leads to conformational changes in tau associated with the formation of PHF and, eventually, NFT (Goedert and Spillantini 2006). Secondary disturbances of the cytoskeleton and alterations in axonal transport can, in turn, compromise the functions and viability of neurons. Eventually, affected nerve cells die (Goedert and Spillantini 2006) and extracellular tangles remain as "tombstones" of the nerve cells destroyed by disease.

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