A Novel APP Knock-In Mouse Model to Study the Protective Effects of the Icelandic Mutation In Vivo

Alzheimer's disease (AD) is the most common form of dementia among people over 65 years old. AD is characterized by the accumulation of β-amyloid (Aβ) plaques in the brain parenchyma and within cerebral vessels (cerebral amyloid angiopathy), hyperphosphorylated intraneuronal neurofibrillary tangles, and loss of synapses. In more than 90% cases, AD occurs sporadically and late in life. The pathological mechanisms for this late-onset AD are still not completely elucidated, but genetic and environmental factors appear to play a significant role. Aging and the presence of the apolipoprotein E (ApoE) ε4 allele are considered the most common risk factors for the disease, but other conditions, including diabetes, high cholesterol, stroke, obesity, and pre-existent cardiovascular diseases, are also significant contributors (Rostagno et al., 2010). In contrast, familial forms of AD (FAD) comprise less than 5–10% of the total AD cases and typically appear before 65 years of age. FAD cases are characterized by mutations in three key genes involved in the generation of Aβ: presenilin (PSEN) 1 and 2 and amyloid precursor protein (APP). More than 300 mutations in these genes have been reported in AD (Rostagno et al., 2010). The dominant linkage of these genes to AD have helped support the original amyloid cascade hypothesis of AD pathogenesis, which considers parenchymal accumulation of Aβ as the crucial initial event that triggers other pathological events. Recent findings have suggested that soluble oligomers of Aβ, rather than monomers or insoluble amyloid fibrils, may be the key initiators of the pathological cascade of events responsible for synaptic dysfunction in the brains of AD patients (Hardy and Selkoe, 2002). Aβ is a peptide generated by sequential cleavage of amyloid precursor protein (APP), first by β-site APP-cleaving enzyme (BACE1) and then by γ-secretase enzymes (amyloidogenic pathway). The main Aβ isoforms involved in neurotoxicity are Aβ40 (40 amino … Correspondence should be addressed to Maria Luisa Valle at maria.valle{at}nyulangone.org.