Although most cases of Alzheimer disease are sporadic and idiopathic, mutations in three genes have been identified as being responsible for a small fraction of early-onset Alzheimer disease, also known as familial Alzheimer disease (FAD). This type of Alzheimer disease accounts for approximately 5% of all Alzheimer disease cases. These genes are those coding for APP,
29 presenilin 1 (PS1, also known as PSEN1), and presenilin 2 (PS2, also known as PSEN2).
30-33 Mutations in the PS1 and PS2 genes account for as much as 50% of all FAD cases.
34 More than 30 mutations in the APP gene and more than 180 mutations in PS1 and PS2 genes have been identified.
35
Other genetic factors leading to FAD include APP locus duplication
36 and polymorphisms in the APP promoter region.
37 Earlier research showed that insoluble fibrillar β-amyloid aggregates were neurotoxic in both in vitro and in vivo conditions, a finding that led to the amyloid cascade hypothesis of Alzheimer disease.
38 Mutations in all three genes were shown to increase the production and aggregation of β-amyloid, an effect that was extensively used to support the amyloid cascade hypothesis.
39
Generation of β-amyloid from APP involves three proteases/secretases—α, β, and γ. Cleavage of APP by β-secretase and γ-secretase produces the β-amyloid peptide, the secreted ectodomain APPsβ, and an intracellular fragment called APP intracellular domain. By contrast, cleavage of APP by α-secretase and γ-secretase results in a p3 peptide, the secreted ectodomain APPsβ, and the APP intracellular domain. Because APP cleavage by α-secretase prevents β-amyloid formation, this process has been called the nonamyloidogenic pathway, and the process involving β-secretase has been named the amyloidogenic pathway.
Although the function of APP, initially identified as the β-amyloid precursor, remains unknown, its deficiency is known to lead to anatomic, physiologic, and behavioral abnormalities in mice. Interestingly, these abnormalities were rescued by the knock-in expression of APP
sβ, suggesting that the APP ectodomain mediates the main functions of APP.
40
The cellular processing of APP and the generation of β-amyloid have long been known,
41 though the identities of the three secretases involved in APP processing have only recently been revealed as a result of advances in molecular and genetics research. Several members of the membrane-bound metalloprotease family—especially those in the ADAM (a disintegrin and metalloprotease) group—have been reported as exhibiting α-secretase activity.
40 Among these metalloproteases, ADAM9, ADAM10, and ADAM17 have been the most intensively investigated.
42 Because α-secretase–mediated APP cleavage reduces β-amyloid generation, a large amount of effort has been invested into developing activators for this group of enzymes.
The protease that exhibits β-secretase activity was identified in 1999 by five research groups and was initially named BACE1 (β-site APP cleaving enzyme 1).
43-48 This protease belongs to the aspartic protease family and is mainly found in the Golgi apparatus and endosomes. Unlike the ADAM proteases, which are ubiquitously expressed in the body, BACE1 is enriched in neurons in the brain. Because down-regulation of BACE1 results in decreased β-amyloid generation, its β-secretase identity is widely accepted.
A study in 1998 identified PS1 as the major component of γ-secretase, based on the finding that PS1 knockout in neurons resulted in an almost complete blockade of β-amyloid generation.
47 Presenilin 2 also exhibits γ-secretase activity.
49 However, subsequent research has shown that, in order for PS1 and its homologue PS2 to function as γ-secretase, their association with three additional proteins—nicastrin, aph-1, and pen-2—is required. Together, these proteins form a tetrameric complex with PS1 and PS2 as the catalytic subunit.
50-53 The reasons that PS1 and PS2 require the other three proteins to function as γ-secretase are not known. Some investigators have proposed that association of PS1 and PS2 with the three additional proteins may facilitate the correct protein assembly, subcellular targeting, and substrate recognition.
Taken together, compelling genetic and molecular evidence supports the amyloid cascade hypothesis for FAD. However, whether the amyloid cascade hypothesis also accounts for sporadic Alzheimer disease remains uncertain. Also unclear is how β-amyloid generation sets in motion the molecular cascade leading to the Alzheimer disease pathologic process.
Since it was first proposed, the amyloid cascade hypothesis has been challenged because of the poor correlation between the number of amyloid plaques that contain fibrillar β-amyloid and the severity of dementia. Furthermore, amyloid plaques have also been reported in individuals who show no cognitive impairment.
54,55 Recent research has indicated that levels of soluble oligomeric β-amyloid exhibit a better correlation than number of amyloid plaques with synaptic loss and severity of cognitive impairment.
55 Additional in vitro studies have shown that various soluble oligomeric species of β-amyloid are more toxic than the fibrillar species.
56
β-amyloid oligomers isolated from brains of individuals with Alzheimer disease show a wide range of molecular weight distribution (ie, from less than 10 kDa to more than 100 kDa). However, the identity of the isoforms responsible for the pathologic process in Alzheimer disease is still under debate. Also remaining unclear is how β-amyloid monomers are converted into oligomers and how oligomers induce neuronal injury. Lauren et al
58 recently reported that β-amyloid oligomers could bind to the cellular prion protein (PrP
c) with nanomolar affinity, suggesting that PrP
c may function as a receptor for β-amyloid oligomers. Binding of β-amyloid oligomers to PrP
c blocked the formation of long-term potentiation, a widely recognized cellular mechanism for certain forms of learning and memory.
59,60 This finding provided a potential mechanism for synaptic dysfunction in Alzheimer disease.
These oligomers have also been shown to disrupt many neuronal functions and to induce cell death by binding to the p75 nerve growth factor receptor,
61-63 the NMDA receptor,
64,65 the insulin receptor,
66,67 and the frizzled receptor.
68 Besides directly interacting with various receptors, β-amyloid oligomers could induce synaptic dysfunction by interacting with scaffold proteins in the postsynaptic density (PSD) region, such as PSD-95 and Shank.
69-71 Furthermore, β-amyloid oligomers can induce cell injury via interaction with endocytic pathways. Still other possibilities that have been proposed for oligomer activity include effects on membrane properties, such as formation of channellike structures,
72,73 and effects causing mitochondrial dysfunction.
74