T714i T714a V715m 1716v

F Indiana G

Figure 11.2 Familial AD Mutations in pAPP. The amino acid sequence of the region of the Amyloid Precursor Protein that contains the Ap peptide is shown with the different secretase sites (a-, p-, y-) marked. The sequence numbering for the Ap peptide is above the sequence while the pAPP sequence numbering is below the sequence. Positions and amino acid changes of the various familial mutations in pAPP are indicated.

eventually forming neurofibrillary tangles, neuropil threads, and vacuolar granules (granulovacuolar degeneration). Tauopathy is first apparent in the entorhinal region, which receives heavy input from the sensory association areas of the neocortex, and then spreads progressively into other limbic structures, the neocortex, and specific subcortical neuronal groups. Senile plaques generally arise after the first tau lesions, and they do not consistently colocalize with neurofibrillary tangles, although there is evidence that they occur in terminal fields of tangle-bearing projection neurons (Schonheit et al., 2004). The stereotypical localization of plaques and tangles suggests the importance of local biochemical conditions and neuronal interconnections in the instigation and spread of the lesions.

While neurofibrillary tangles become evident prior to senile plaques in aging humans, there is growing evidence that the anomalous aggregation of A^ is a seminal event in AD pathogenesis (Hardy and Selkoe, 2002; Walker and LeVine, 2002) and that the corruption of tau occurs in response to initial abnormalities of A^ (Walker and LeVine, 2002; Oddo et al., 2004). Three compelling arguments support the primacy of A^ in the

Alzheimer's disease cascade: (1) The large quantity of Aß deposits in the AD brain implicates the peptide in pathogenesis; (2) the most common autosomal dominant forms of AD all involve mutations either in the ß-amyloid precursor protein (ßAPP) (Figure 11.2) (Revesz et al., 2003) or in the presenilins (PS1 and PS2, which form the probable catalytic subunit of the gamma-secretase complex that liberates Aß at its C-terminus (Marjaux et al., 2004); and (3) all known genetic and environmental risk factors for AD increase the production of Aß and/or its tendency to aggregate (Hardy and Selkoe, 2002).

According to the Aß-cascade hypothesis, the abnormal accumulation of multimeric Aß triggers a progression of events leading to amyloid plaques, neurofibrillary tangles, inflammation, neuron- and synapse loss, and dementia. In vitro and in vivo studies are beginning to implicate a prefibrillar, oligomeric form of Aß in this cascade (Kayed et al., 2003). Indeed, the major genetic risk factor for AD (accounting for over 50% of the risk) is the inheritance of the s4 allele of apolipoprotein-E (ApoE); ApoEfi4 is associated with increased Aß(1-42) while decreasing the age of disease onset (Poirier, 1994).

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