Neurochemical Mechanisms in Disease P72 doc

The Genetics of Alzheimer’s Disease
and Parkinson’s Disease
Lynn M. Bekris, Chang-En Yu, Thomas D. Bird, and Debby Tsuang
Abstract Alzheimer’s disease (AD) is the most common neurodegenerative disor-
der. It is characterized by progressive loss of memory and other cognitive domains
along with functional decline that can occur in the third to eighth decades. The early
onset (<60 years old) familial forms of AD have an autosomal dominant inheri-
tance linked to three causative genes: APP, PSEN1, and PSEN2. The most common
sporadic form of AD occurs after the age of 60 and is associated with the APOE
gene. The mechanistic contribution of these genes in AD pathogenesis has been
studied extensively but is still unclear, suggesting that other AD associated genes
remain to be elucidated. Parkinson’s disease (PD) i s the second most common neu-
rodegenerative disorder. Idiopathic PD is the most frequent form of Parkinsonism,
although rare forms of PD in which genetic factors dominate exist. Family stud-
ies have identified 13 causative genetic loci linked to PD of which 8 genes have
been described: four autosomal dominant (SNCA, LRRK2, UCHL1, and HTRA2)
and four autosomal recessive (PRKN, DJ1, PINK1, and ATP13A2). In addition,
another gene has recently been described as a possible risk factor for PD (GBA).
The function of these genes and their contribution to PD pathogenesis remains to be
fully elucidated. Like AD, other genes that contribute to PD risk likely exist. The
prevalence, incidence, clinical manifestations, and genetic components of these two
neurodegenerative disorders, AD and PD, are discussed in this chapter.
Keywords Alzheimer’s disease · Parkinson’s disease · Presenilin · Amyloid
precursor protein · Apolipoprotein E · Synuclein · Parkin · LRRK2 · PINK1 ·
neurodegeneration
Contents
1 Alzheimer’s Disease 696
1.1 Introduction
696
D. Tsuang (B)
Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine,

Seattle, WA, USA; Mental Illness Research, Education and Clinical Center, Veterans Affairs Puget
Sound Health Care System, Seattle, WA, USA
e-mail:
695
J.P. Blass (ed.), Neurochemical Mechanisms in Disease,
Advances in Neurobiology 1, DOI 10.1007/978-1-4419-7104-3_21,
C

Springer Science+Business Media, LLC 2011
696 L.M. Bekris et al.
1.2 Genetics of Alzheimer’s Disease
699
1.3 Summary
711
2 Parkinson’s Disease
711
2.1 Introduction
711
2.2 Genetics of Parkinson’s Disease
712
2.3 Summary
731
References
732
1 Alzheimer’s Disease
1.1 Introduction
1.1.1 Prevalence and Incidence
Alzheimer’s disease (AD) (OMIM #104300) is the most common irreversible, pro-
gressive brain disease. It is characterized by a gradual loss of memory and cognitive
skills. AD accounts for over 50% of all dementia cases, and presently affects more

than 24 million people worldwide, with over 5 million new cases each year, a figure
that is likely to increase as a greater proportion of the population ages (Ferri et al.,
2005).
Age is the largest known risk factor, with AD prevalence increasing significantly
with age. AD incidence increases from 2.8 per 1000 person-years when 65–69 years
and to 56.1 per 1000 person-years when older than 90 years (Kukull et al., 2002).
Approximately 10% of persons older than 70 years have significant memory loss
and more than half of these individuals have probable AD. An estimated 25–45%
of persons older than 85 years have dementia (Bird, 2008). The duration of disease
is typically 8–10 years, with a range from 2 to 25 years after diagnosis. The disease
is divided into two subtypes based on the age of onset: early-onset AD (EOAD) and
late-onset AD (LOAD). EOAD accounts for approximately 1–6% of all cases and
ranges roughly from 30 years to 60 or 65 years. On the other hand, the most com-
mon form of AD, LOAD, is defined as an age-at-onset later t han 60 or 65 years. Both
EOAD and LOAD may have a positive family history of AD. With the exception of
a few autosomal dominant families that are single-gene disorders (see below), most
AD appears to be a complex disorder that is likely to involve multiple susceptibility
genes and environmental factors (Bertram and Tanzi, 2004b;Bird,2008; Kamboh,
2004; Roses, 2006; Serretti et al., 2005). Approximately 60% of EOAD is famil-
ial, with multiple cases of AD within a family. Thirteen percent of these familial
cases are inherited in an autosomal dominant manner with at least three generations
affected (Brickell et al., 2006; Campion et al., 1999). Early-onset cases can also
occur in families with late-onset disease (Bird, 2008).
1.1.2 Clinical Symptoms
Both EOAD and LOAD present clinically as dementia that begins with a gradual
decline of memory which slowly increases in severity until symptoms eventually
Genetics of AD and PD 697
become incapacitating. Other common symptoms are confusion, poor judgment,
language disturbance, agitation, withdrawal, and hallucinations. Rare symptoms
include seizures, Parkinsonism, increased muscle tone, myoclonus, incontinence,

and mutism. Death commonly occurs from general inanition, malnutrition, and
pneumonia (Bird, 2008). Treatment of AD with cholinesterase inhibitors and
memantine may have some improvement in cognitive decline in mild to moder-
ate dementia cases but overall there is clinically marginal improvement in measures
of cognition and global assessment of dementia (Raina et al., 2008; Raschetti et al.,
2007).
1.1.3 Clinical Diagnosis
Currently, the diagnosis of AD is based on clinical history and neuropsycho-
logical tests. The Diagnostic and Statistical Manual of Mental Disorders, 4th
Edition (DSM-IV) criteria for diagnosing dementia requires loss of two or more
of the following: memory, language, calculation, orientation, or judgment (Kawas,
2003). The Mini-Mental State Examination (MMSE) helps to evaluate changes in
a patient’s cognitive abilities. In addition, a diagnosis of probable AD necessitates
the exclusion of other degenerative disorders associated with dementia, such as fron-
totemporal dementia (including frontotemporal dementia with Parkinsonism-17 and
Pick’s disease), Parkinson’s disease, diffuse Lewy body disease, Creutzfeldt–Jakob
disease, and cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL) (Rogan and Lippa, 2002). Discrimination f rom
other forms of dementia is usually based on clinical history and neuroimaging (Bird,
2008). In addition, other possible causes of dementia also need to be excluded,
especially the treatable forms of cognitive impairment, such as that due to depres-
sion, chronic drug intoxication, chronic central nervous system infection, thyroid
disease, vitamin deficiencies (i.e., B
12
and thiamine), central nervous system angi-
tis, and normal-pressure hydrocephalus (Bird, 2008). Individuals who do not meet
these criteria but have short-term memory loss and have only minimal impairment
in other cognitive abilities and are not functionally impaired at work or at home are
considered to have “mild cognitive impairment” (Petersen et al., 2001).
1.1.4 Neuropathological Diagnosis

A definitive diagnosis of AD requires not only the presence of severe dementia
in life but also postmortem confirmation, with the presence of two histopathologi-
cal features: neurofibrillary tangles and amyloid plaques (Braak and Braak, 1997;
Goedert and Spillantini, 2006; Nussbaum and Ellis, 2003). The clinical diagno-
sis of AD, before autopsy confirmation, is correct about 80–90% of the time by
expert clinicians (Kaye, 1998). Even though plaques and tangles are often also
found in cognitively normal age-matched controls, the density and distribution are
more severe in patients with AD, according to standardized histological assessments
(Braak and Braak, 1997). Amyloid plaques are extracellular with a cross-beta struc-
ture and characteristic dye-binding (neuritic amyloid plaques contain thioflavin S
and Congo red-positive fibrillar deposits with both Aβ40 and Aβ42 present; Kidd,
698 L.M. Bekris et al.
Fig. 1 APP cleavage. The APP protein can be cleaved by three different secretases: α, β,orγ
(panel a). Subsequent to “normal” α-secretase cleavage, sAPP α is produced and released into the
extracellular space and the C83 peptide remains in the cell membrane (panel b). Subsequent to β-
secretase cleavage, sAPPβ is produced and released into the extracellular space and the C99 peptide
remains in the cell membrane (panel c). Subsequent to β-secretase cleavage, the C99 peptide is
“abnormally” cleaved by γ-secretase to yield an Aβ peptide and the AICD peptide (panel d). Scale
is approximate
1963; Terry et al., 1964). The major component of amyloid plaques is amyloid-beta
(Aβ), which can be stained and detected using Aβ antibodies (Glenner et al., 1984;
Iwatsubo et al., 1994). The most common form of Aβ is 40 amino acids long and
is called Aβ40. A 42 amino acid long fragment, Aβ42, is less abundant and differs
only by having two additional amino acid residues at the C-terminus. Aβ42 is asso-
ciated with AD (Bentahir et al., 2006). Aβ is derived from the amyloid precursor
protein (APP) by the action of two aspartyl proteases. First α-secretase (nonneuro-
toxic “normal” cleavage) or β-secretase (potential neurotoxic “abnormal” cleavage)
cleaves APP (Fig. 1). Second γ-secretases cleave APP (Haass et al., 1992; Seubert
et al., 1992; Shoji et al., 1992). Upon cleavage by α-secretase, a large ectodomain
referred t o as soluble APP alpha (sAPPα) is released and a C-terminal 83 amino

acid f ragment (C83) remains membrane bound. Upon cleavage by β-secretase, APP
sheds a large ectodomain referred to as soluble APP beta (sAPPβ) and leaves a
membrane-bound C-terminal fragment (Cai et al., 2001; Vassar et al., 1999). This
99 amino acid fragment (C99) is membrane bound and is subsequently cleaved by
γ-secretase to release Aβ and the APP intracellular domain (AICD) (De Strooper,
2000; Schroeter et al., 2003) (Fig. 1). Thus two main forms of Aβ are produced
Genetics of AD and PD 699
depending on the point of cleavage by γ-secretase; producing either 40 or 42 amino
acid residues. The proportion of Aβ42 to Aβ40 formed is particularly important in
AD because Aβ42 is far more prone to oligomerize and form fibrils than the more
abundantly produced Aβ40 peptide. In a small number of individuals an increased
proportion of Aβ42 appears sufficient to cause EOAD even though it appears that
the production of Aβ isoforms is a normal process of unknown function (Goedert
and Spillantini, 2006; Irvine et al., 2008).
Neurons bearing neurofibrillary tangles containing hyperphosphorylated tau are
frequently found in AD brain (Kosik et al., 1986; Wood et al., 1986), and their tem-
poral and spatial appearance more closely reflects disease severity than does the
presence of amyloid plaques (Braak and Braak, 1991; Thal et al., 2006). However,
neurofibrillary tangles are not specific to AD, are found in other disorders (such as
frontotemporal dementia and progressive supranuclear palsy), and are not neces-
sarily associated with the cognitive dysfunction and memory impairment typical of
AD, and mutations in the gene that encodes the tau protein (MAPT) have not been
genetically linked to AD (Iwatsubo et al., 1994).
1.2 Genetics of Alzheimer’s Disease
1.2.1 Introduction
To date autosomal dominant early-onset familial AD (EOFAD) is associated with
three genes: the APP gene, the presenilin 1 gene (PSEN1), and the presenilin 2 gene
(PSEN2) (Goedert and Spillantini, 2006). However, it is likely that other genes will
be identified as a cause of EOFAD because there are still kindreds with autosomal-
dominant EOFAD with no known mutations in these three genes (Bird, 2008;Cruts

and Van Broeckhoven, 1998; Raux et al., 2005). Despite evidence from family stud-
ies that genetic mutations cause EOFAD, more than 90% of AD cases appear to
be sporadic, without a family history, and have a later age-at-onset of 60–65 years
(Bertram and Tanzi, 2004a). The only gene consistently found to be associated with
sporadic LOAD, across multiple studies, is the apolipoprotein E gene (APOE) (Coon
et al., 2007; Couzin, 2008; Roses et al., 1995; Schellenberg, 1995; Selkoe, 2001)
(Table 1). Although twin studies support the existence of a genetic component in
LOAD, no causative gene has been yet identified. The age-at-onset of LOAD is
significantly more variable for dizygotic twins than for monozygotic twins, sug-
gesting that both genetic and environmental factors play a role in the disease (Gatz
et al., 2006). The APOE gene is the only well-validated gene strongly associated
with LOAD risk (Coon et al., 2007; Couzin, 2008; Roses et al., 1995; Schellenberg,
1995; Selkoe, 2001). However, many carriers of the APOE risk allele (4) live into
their 90s, suggesting the existence of other LOAD genetic and/or environmental risk
factors yet to be identified. Several other genetic variants have been reported and
suggest that there may be five to seven major LOAD susceptibility genes, but most
are without replication among studies (Bird, 2008; Chai, 2007; Daw et al., 2000).
For a catalogue of candidate gene association studies, please refer to the AlzGene
online database ( />700 L.M. Bekris et al.
Table 1 Alzheimer’s disease and Parkinson’s disease genes. Alzheimer’s disease genes; AD1–4
(panel A) and Parkinson’s disease genes; PARK1–13 (panel B)
1.2.2 Genes Associated with Autosomal Dominant Alzheimer’s Disease
AD1: App
Inheritance and Clinical Features
The purification of both plaque and vascular amyloid deposits and the isolation of
their 40-residue constituent peptide (Aβ) led to the cloning of the APP type I inte-
gral membrane glycoprotein from which Aβ is proteolytically derived (Kang et al.,
1987). The APP gene was mapped to chromosome 21q which accounts for the
observation that Down syndrome patients (trisomy 21) develop amyloid deposits
and the neuropathological features of AD in their 40 s (Giaccone et al., 1989;

Iwatsubo et al., 1994; Lemere et al., 1996; Mann et al., 1989). Subsequent searches
for autosomal dominant EOAD families with genetic linkage to chromosome 21
resulted in the identification of six different missense mutations in APP, five associ-
ated with familial AD (Chartier-Harlin et al., 1991a, b;Goateetal.,1991; Mullan,
1992; Murrell et al., 1991), and one with the neuropathologically related syndrome
of hereditary cerebral hemorrhage with amyloidosis of the Dutch type (Levy et al.,
1990).
Subsequently, over 20 different APP missense mutations have been identified
in 60 families. Interestingly, most of these mutations are located at exons 16
and 17 where the secretase cleavage sites or the APP transmembrane domain are
located (Fig. 2). Information regarding APP mutations is available in the NCBI
database and the Alzheimer Disease Mutation Database (www.molgen.ua.ac.be/
ADMutations) (Cruts and Van Broeckhoven, 1998). Mutations within APP account
for 10–15% of EOFAD (Bird, 2008; Janssen et al., 2003; Raux et al., 2005;
Sherrington et al., 1996), appear to be family specific, and do not occur within the
Genetics of AD and PD 701
Fig. 2 AD1: APP structure and mutations. SP, signal peptide; KPI, Kunitz protease inhibitor
domain; Aβ, amyloid beta; TM, transmembrane domain. Scale is approximate
majority of sporadic AD cases. The majority of these EOFAD mutations are located
in or adjacent to the Aβ peptide sequence (Fig. 2), the major component of the amy-
loid plaques (Esler and Wolfe, 2001; Suzuki et al., 1994). Most cases containing
APP mutations have an age of onset in the mid-40 s and 50 s ( Hardy, 2001).
Gene Location and Structure
Sequences encoding APP were first cloned by screening cDNA libraries (Kang
et al., 1987). The i nitial full-length cDNA clone encoded a 695 amino acid protein
(APP695) (Schellenberg, 1995) and consisted of 18 exons. The APP gene, located
at chromosome 21q21, is alternatively spliced into several products, named accord-
ing to their length in amino acids (i.e., APP695, APP714, APP751, APP770, and
APP563) and expressed differentially by tissue type whereby three isoforms, most
relevant to AD, are restricted to the central nervous system (APP695) or expressed

in both the peripheral and CNS tissues (APP751 and APP770) (de Sauvage and
Octave, 1989; Golde et al., 1990; Goldgaber et al., 1987; Kang et al., 1987;
Kitaguchi et al., 1988; Ponte et al., 1988; Tanzi et al., 1988; Yoshikai et al., 1990).
Gene Function and Expression
APP is a type I integral membrane protein (Kang et al., 1987) that resembles a
signal-transduction receptor. It is expressed in many tissues and concentrated in the
702 L.M. Bekris et al.
synapses of neurons. Its primary function is not known, although it has been impli-
cated in neural plasticity (Turner et al., 2003) and as a regulator of synapse formation
(Priller et al., 2006). APP is synthesized in the ER, posttranscriptionally modified
in the Golgi (N- and O-linked glycosylation, sulfation, and phosphorylation), and
transported to the cell surface via the secretory pathway. APP is also endocytosed
from the cell surface and processed in the endosomal–lysosomal pathway (Bossy-
Wetzel et al., 2004; Koo and Squazzo, 1994). APP and Aβ have been found to
be translocated inside mitochondria and implicated in mitochondrial dysfunction
(Anandatheerthavarada et al., 2003; Devi et al., 2006; Lin and Beal, 2006).
Proteolysis of APP by α-secretase or β-secretase leads to the secretion of sAPPα
or sAPPβ. This proteolysis generates C-terminal fragments of 10 kDa and 12 kDa,
respectively, which are inserted into the membrane. These fragments can be cut
by γ-secretase to release the Aβ peptide extracellularly (Walter et al., 2001) and a
cytoplasmic fragment identified as AICD intracellularly (Sastre et al., 2001) (Fig. 1).
Intriguingly, AICD starts at position 49/50 and does not correspond to the end of
Aβ variants Aβ40 and Aβ42. Therefore this cleavage site has been termed the -
cleavage site, and interestingly, it is topologically highly similar to the S3 cleavage
of Notch (Sastre et al., 2001; Weidemann et al., 2002). Recently, a new cleavage site
was described for γ-secretase. The ξ-cleavage occurs between the - and γ-cleavage
sites and generates longer Aβ isoforms within cells and in the brain, including Aβ43,
Aβ45, Aβ46, and Aβ48 (Qi-Takahara et al., 2005; Zhao et al., 2004). The majority
of EOAD mutations alter this processing of APP in such a way that Aβ
42 levels

relative to other Aβ isoforms are changed (Scheuner et al., 1996; Walker et al.,
2005). The function of these APP proteolytic fragments is still unclear.
The missense APP “Swedish” mutations (APPSW, APPK670N, and M671L) and
the “London” mutations (APPLON and APPV717I) are examples of APP muta-
tions that lead to increased Aβ production and development of AD (Goate et al.,
1991; Mullan, 1992). Transgenic mouse models of APP mutations have been devel-
oped such as: PDAPP, Tg2576, APP23, TgCRND8, and J20 ( Higgins and Jacobsen,
2003). Each of these transgenic mouse models has different mutations and dif-
ferent promoters that lead to different expression levels and different levels of
neuroanatomical abnormalities (Higgins and Jacobsen, 2003; Mineur et al., 2005).
For example, the Tg2576 mouse model that carries the “Swedish” mutation has high
APP levels, high Aβ levels, and cognitive disturbances (Irizarry et al., 1997) that are
progressive and start as early as six months of age (Westerman et al., 2002).
Genetic Variation
APP transcripts have been identified in which exons 7, 8, and 15 are alternatively
spliced. Exon 7 encodes 57 amino acids with homology to the Kunitz-type protease
inhibitor (KPI) domain (Kitaguchi et al., 1988; Ponte et al., 1988; Tanzi et al., 1988)
and exon 8 (Kitaguchi et al., 1988; Lemaire et al., 1989). The Aβ peptide is encoded
by parts of both exons 16 and 17 (exon and codon numbering based on the APP770
splice variant) (Lemaire et al., 1989) (Fig. 2). In neurons, t he predominant isoform
is APP695 (Weidemann et al., 1989), which contains exon 15 but excludes exons
Genetics of AD and PD 703
7 and 8. The major isoforms in peripheral tissue (APP751 and APP770), and also
in neurons, encode KPI-containing forms of APP (Kitaguchi et al., 1988; Ponte
et al., 1988; Sandbrink et al., 1994; Tanzi et al., 1988). Other splice variants have
been observed that are missing exon 15 in various combinations with exons 7 and
8 and are referred to as L-APPs (Konig et al., 1991; Sandbrink et al., 1994). A
number of studies have indicated that alternative splicing of exons 7 and 8 in APP
mRNAs is changed in the brain during aging and possibly during AD (Johnson
et al., 1989; Konig et al., 1991; Neve et al., 1988; Palmert et al., 1988; Sisodia

et al., 1990; Tanaka et al., 1988). Even though the function of APP and its various
splice variants is unknown, differential expression of these splice variants between
tissues may imply functional differences. It is important to note that although most
of the described splice variants contain Aβ-encoding sequences, two additional rare
transcripts, APP365 and APP563, do not, implicating additional variability in APP
function (de Sauvage and Octave, 1989; Jacobsen et al., 1991).
The first described and best characterized APP mutation (V717I) was identi-
fied in a London family and is located within the transmembrane domain near the
γ-secretase cleavage site (Goate et al., 1991) (Fig. 2). Subsequently, other substi-
tutions at this site have been identified and many other groups have reported the
V717I mutation in other families. Many other mutations have been identified, most
of which are located near the gamma-secretase cleavage site and have been associ-
ated with modulation of Aβ levels. For example, a C-terminal L723P mutation was
identified in an Australian family and is reported to generate an increase of Aβ42
peptide levels in CHO cells (Kwok et al., 2000). The majority of EOAD mutations
alter processing of APP in such a way that the relative level of Aβ42 is increased,
either by increasing Aβ42 or decreasing Aβ40 peptide l evels or both (Scheuner et al.,
1996; Walker et al., 2005).
AD3: Presenilin 1
Inheritance and Clinical Features
Linkage studies established the presence of an AD3 locus on chromosome 14
(Schellenberg et al., 1992) and positional cloning led to the identification of muta-
tions in the PSEN1
gene, which encodes a polytopic membrane protein (Sherrington
et al., 1995). Presenilins are major components of the atypical aspartyl protease
complexes responsible for the γ-secretase cleavage of APP (De Strooper et al.,
1998; Wolfe et al., 1999b). Mutations in PSEN1 are the most common cause of
EOFAD. PSEN1 missense mutations account for 18–50% of the autosomal domi-
nant EOFAD (Theuns et al., 2000). PSEN1 mutations appear to increase the ratio
of Aβ42 to Aβ40, and this appears to result in a change in function that leads to

reduced γ-secretase activity (Citron et al., 1997). In preclinical cases with PSEN1
mutations, deposition of Aβ42 may be an early event (Lippa et al., 1998).
Defects in PSEN1 cause the most severe forms of AD, with complete pen-
etrance and an onset occurring as early as 30 years of age. A second form
of PSEN1-associated AD has a mean age of onset greater than 58 years. Both
are autosomal dominant neurodegenerative disorders characterized by progressive
704 L.M. Bekris et al.
dementia, Parkinsonism, and notch signaling, as well as Aβ intracellular domain
generation (Goedert and Spillantini, 2006;Wolfe,2007). There is considerable phe-
notypic variability in EOFAD, including some patients with spastic paraparesis and
other atypical AD symptoms. Some of these variable clinical phenotypes have been
described by specific mutations. Neuropathological studies often confirm the clin-
ical diagnosis of AD with measurement of amyloid plaque and Braak stage (as
described above) but vary in other brain areas according to the presence of specific
PSEN1 mutations (Moehlmann et al., 2002; Rudzinski et al., 2008). For example,
clinical and neuropathologic features of a Greek family with a PSEN1 mutation
(N135S) include memory loss in their 30 s, as well as variable limb spasticity and
seizures. Upon neuropathological examination, the diagnosis of AD was confirmed
but in addition, there was histological evidence of corticospinal tract degeneration
(Rudzinski et al., 2008). A PSEN1 mutation (I143M) that lies in a cluster in the sec-
ond transmembrane domain of the protein has been described in an African family
with an age-at-onset in the early 50 s that lasts for 6–7 years. Neuropathologically,
these cases were characterized by neuronal loss, abundant Aβ neuritic plaques,
and neurofibrillary tangles as well as degeneration extending into the brainstem
(Heckmann et al., 2004).
Gene Location and Structure
PSEN1 is located on chromosome 14q24.2 and consists of 12 exons that encode a
467 amino acid protein that is predicted to traverse the membrane 6–10 times; the
amino and carboxyl termini are both oriented toward the cytoplasm (Hutton and
Hardy, 1997).

Gene Function and Expression
PSEN1 is a polytopic membrane protein that forms the catalytic core of the gamma-
secretase complex (De Strooper et al., 1998; Wolfe et al., 1999a). Gamma-secretase
is an integral membrane protein found at the cell surface, but it may also be found
in the Golgi, endoplasmic reticulum, and mitochondria (Baulac et al., 2003;De
Strooper et al., 1998). PSEN1, nicastrin (Nct), anterior pharynx defective 1 (Aph-
1), and presenilin enhancer 2 (PSENEN) are required for the stability and activity
of the γ-secretase complex (Edbauer et al., 2003; Francis et al., 2002; Goutte et al.,
2002; Kimberly et al., 2003; Takasugi et al., 2003). This complex cleaves many
type I transmembrane proteins including APP and Notch (De Strooper et al., 1999,
1998) in the hydrophobic environment of the phospholipid bilayer of the membrane
(Kimberly et al., 2003). Gamma-secretase is biologically and biochemically hetero-
geneous, consisting of four and potentially more different complexes that result from
the mutually exclusive incorporation of PSEN1, PSEN2, and PSENEN or Aph-1-A
and Aph-1-B protein subunits (Kimberly et al., 2003; Serneels et al., 2005). PSEN1
knock-out mice are not viable (Shen et al., 1997) but a conditional PSEN1 knock-out
mouse model, where the loss of the gene is limited to the postnatal forebrain, shows
mild cognitive impairments in long-term spatial reference memory and retention (Yu
et al., 2001
), suggesting that presenilins play a role in cognitive memory. Knock-in