Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein E depends on isoform, aging, and overexpression of amyloid β peptides but not on plaque formation

“Because synaptic deficits correlate well with the development of cognitive deficits in AD (DeKosky and Scheff, 1990; Terry et al., 1991; Langlais et al., 1993; Samuel et al., 1997; Sze et al., 1997; Brown et al., 1998), the differential effects of apoE3 and apoE4 identified here might relate closely to the effects of…”

“These associations have widely been interpreted as evidence that apoE4 increases AD risk through its effect on amyloid deposition (Holtzman et al., 2000a,b; Selkoe, 2001).”

“We focused our analysis on SYN-IR presynaptic terminals, choline acetyltransferase (ChAT) activity, and cholinergic fibers, because decreases in these parameters correlate well with cognitive decline in AD (Terry et al., 1991; Samuel et al., 1997; Sze et al., 1997; Brown et al., 1998).”

“…evidence is mounting that ADrelated synaptic degeneration and functional neuronal impairments may be caused primarily by nondeposited forms of A (Lambert et al., 1998; Hartley et al., 1999; Holcomb et al., 1999; Hsia et al., 1999; Lue et al., 1999; McLean et al., 1999; Mucke et al., 2000; Raber…”

“…(Pike et al., 1993; Yankner, 1996; Klein et al., 2001), injected into the brain (Geula et al., 1998), or produced in neurons of transgenic mice (Games et al., 1995; Masliah et al., 1996, 2001; Nalbantoglu et al., 1997; Calhoun et al., 1998; Price et al., 1998; Hsia et al., 1999; Mucke et al.,…”

“Because synaptic deficits correlate well with the development of cognitive deficits in AD ( DeKosky and Scheff, 1990; Terry et al., 1991; Langlais et al., 1993; Samuel et al., 1997; Sze et al., 1997; Brown et al., 1998), the differential effects of apoE3 and apoE4 identified here might relate closely to the effects of…”

“Its activity is 40–90% lower in AD brains than in control brains, and this reduction correlates with cognitive decline (Perry et al., 1978; Davies, 1979; Wilcock et al., 1982; Sims et al., 1983; Neary et al., 1986; Bierer et al., 1995; Samuel et al., 1997; Cummings, 2000).”

“…terminals in hAPP mice expressing high levels of soluble human A On the murine apoE wild-type background, hAPP mice develop an age-dependent loss of SYN-IR presynaptic terminals that is associated with major deficits in synaptic transmission strength (Hsia et al., 1999; Mucke et al., 2000).”

“…and A -dependent synaptic deficits include promotion of neurite extension (Nathan et al., 1994; Holtzman and Fagan, 1998) and synapse formation (Mauch et al., 2001), stabilization of microtubules (Strittmatter et al., 1994; Nathan et al., 1995) and endosomal–lysosomal membranes (Ji et al.,…”

“…and in hAPP transgenic mice have demonstrated that AD-related synaptic and functional neuronal deficits correlate better with levels of nondeposited A than with plaque load (Holcomb et al., 1999; Hsia et al., 1999; Lue et al., 1999; McLean et al., 1999; Mucke et al., 2000; Raber et al., 2000).”

“The two most frequent isoforms differ not only in their effects on A deposition (E4 E3) (Rebeck et al., 1993; Schmechel et al., 1993; Berr et al., 1994; Heinonen et al., 1995; Hyman et al., 1995; Gearing et al., 1996; Ishii et al., 1997; Johnson et al., 1998; McNamara et al., 1998; Holtzman et al.,…”

“Human A is neurotoxic when added to cultures of neural cells or tissue sections (Pike et al., 1993; Yankner, 1996; Klein et al., 2001), injected into the brain (Geula et al., 1998), or produced in neurons of transgenic mice (Games et al., 1995; Masliah et al., 1996, 2001; Nalbantoglu et al., 1997;…”

“…to have relatively little impact on the severity and progression of neuronal deficits in old age and during later stages of AD (Farrer et al., 1997; Bookheimer et al., 2000; Greenwood et al., 2000; Small et al., 2000; Yaffe et al., 2000; Caselli et al., 2001; Chapman et al., 2001; Reiman et al.,…”

“…is responsible for the dysfunction and degeneration of neurons in AD remains a matter of active study and debate (Terry, 1996; Davis and Chisholm, 1997; Hartley et al., 1999; Hsia et al., 1999; Lue et al., 1999; McLean et al., 1999; Mucke et al., 2000; Näslund et al., 2000; Klein et al., 2001).”

“…terminals in hAPP mice expressing high levels of soluble human A On the murine apoE wild-type background, hAPP mice develop an age-dependent loss of SYN-IR presynaptic terminals that is associated with major deficits in synaptic transmission strength (Hsia et al., 1999; Mucke et al., 2000).”

“The two most frequent isoforms differ not only in their effects on A deposition (E4 E3) (Rebeck et al., 1993; Schmechel et al., 1993; Berr et al., 1994; Heinonen et al., 1995; Hyman et al., 1995; Gearing et al., 1996; Ishii et al., 1997; Johnson et al., 1998; McNamara et al., 1998; Holtzman et al.,…”

“Human A is neurotoxic when added to cultures of neural cells or tissue sections (Pike et al., 1993; Yankner, 1996; Klein et al., 2001), injected into the brain (Geula et al., 1998), or produced in neurons of transgenic mice (Games et al., 1995; Masliah et al., 1996, 2001; Nalbantoglu et al., 1997;…”

“…is responsible for the dysfunction and degeneration of neurons in AD remains a matter of active study and debate (Terry, 1996; Davis and Chisholm, 1997; Hartley et al., 1999; Hsia et al., 1999; Lue et al., 1999; McLean et al., 1999; Mucke et al., 2000; Näslund et al., 2000; Klein et al., 2001).”

“Human A is neurotoxic when added to cultures of neural cells or tissue sections (Pike et al., 1993; Yankner, 1996; Klein et al., 2001), injected into the brain (Geula et al., 1998), or produced in neurons of transgenic mice (Games et al., 1995; Masliah et al., 1996, 2001; Nalbantoglu et al., 1997;…”

“…Berr et al., 1994; Heinonen et al., 1995; Hyman et al., 1995; Gearing et al., 1996; Ishii et al., 1997; Johnson et al., 1998; McNamara et al., 1998; Holtzman et al., 2000a,b) but also in their capacity to protect the brain against diverse injuries, including those elicited by excitotoxins,…”

“…extension (Nathan et al., 1994; Holtzman and Fagan, 1998) and synapse formation (Mauch et al., 2001), stabilization of microtubules (Strittmatter et al., 1994; Nathan et al., 1995) and endosomal–lysosomal membranes (Ji et al., 2002), and protection against oxidative stress (Miyata and Smith, 1996).”

“It is expressed at high levels in the brain and can be produced by diverse cell types, including neurons, astrocytes, and microglia (Boyles et al., 1985; Stone et al., 1997; Buttini et al., 1999; Xu et al., 1999, 2000; Dekroon and Armati, 2001).”

“This finding may be consistent with the notion that the formation of neurotoxic A species depends on the association of A with “pathological molecular chaperones,” such as apoE and apoJ (Wisniewski and Frangione, 1992; Oda et al., 1995; Ma et al., 1996; Permanne et al., 1997).”

“Neuroprotective activities of apoE3 that might allow it to delay age- and A -dependent synaptic deficits include promotion of neurite extension (Nathan et al., 1994; Holtzman and Fagan, 1998) and synapse formation (Mauch et al., 2001), stabilization of microtubules (Strittmatter et al., 1994;…”

“…4 alleles but without overt AD revealed decreased brain activity, decreased visual attention, and subtle memory impairments in 4 carriers compared with people with other APOE alleles (Caselli et al., 1999; Bookheimer et al., 2000; Greenwood et al., 2000; Small et al., 2000; Reiman et al., 2001).”

“Frozen brain tissues were homogenized in guanidine buffer, and human A peptides were quantitated by ELISA as described previously (Johnson-Wood et al., 1997).”

“Its activity is 40 –90% lower in AD brains than in control brains, and this reduction correlates with cognitive decline (Perry et al., 1978; Davies, 1979; Wilcock et al., 1982; Sims et al., 1983; Neary et al., 1986; Bierer et al., 1995; Samuel et al., 1997; Cummings, 2000).”

“In the presence of murine apoE (Hsia et al., 1999; Mucke et al., 2000; Masliah et al., 2001) or human apoE (this study), A clearly did affect the integrity or function of presynaptic terminals and cholinergic neurons.”

“However, biochemical and neuropathological alterations of the cholinergic system have been detected primarily in later stages of the disease, and their modification by apoE isoforms remains controversial (Poirier et al., 1995; Soininen et al., 1995; Allen et al., 1997; Arendt et al., 1997; Salehi et al., 1998; Gilmor…”

“Its activity is 40–90% lower in AD brains than in control brains, and this reduction correlates with cognitive decline (Perry et al., 1978; Davies, 1979; Wilcock et al., 1982; Sims et al., 1983; Neary et al., 1986; Bierer et al., 1995; Samuel et al., 1997; Cummings, 2000).”

“We focused our analysis on SYN-IR presynaptic terminals, choline acetyltransferase (ChAT) activity, and cholinergic fibers, because decreases in these parameters correlate well with cognitive decline in AD (Terry et al., 1991; Samuel et al., 1997; Sze et al., 1997; Brown et al., 1998).”

“Its activity is 40–90% lower in AD brains than in control brains, and this reduction correlates with cognitive decline (Perry et al., 1978; Davies, 1979; Wilcock et al., 1982; Sims et al., 1983; Neary et al., 1986; Bierer et al., 1995; Samuel et al., 1997; Cummings, 2000).”

“…when added to cultures of neural cells or tissue sections (Pike et al., 1993; Yankner, 1996; Klein et al., 2001), injected into the brain (Geula et al., 1998), or produced in neurons of transgenic mice (Games et al., 1995; Masliah et al., 1996, 2001; Nalbantoglu et al., 1997; Calhoun et…”

“…et al., 1993; Yankner, 1996; Klein et al., 2001), injected into the brain (Geula et al., 1998), or produced in neurons of transgenic mice (Games et al., 1995; Masliah et al., 1996, 2001; Nalbantoglu et al., 1997; Calhoun et al., 1998; Price et al., 1998; Hsia et al., 1999; Mucke et al., 2000).”

“…effects of apoE3 and apoE4 on the development of AD manifestations were apparent primarily during early but not late stages of the aging process (Farrer et al., 1997; Bookheimer et al., 2000; Greenwood et al., 2000; Small et al., 2000; Yaffe et al., 2000; Chapman et al., 2001; Reiman et al., 2001).”

“…of neurite extension (Nathan et al., 1994; Holtzman and Fagan, 1998) and synapse formation (Mauch et al., 2001), stabilization of microtubules (Strittmatter et al., 1994; Nathan et al., 1995) and endosomal–lysosomal membranes (Ji et al., 2002), and protection against oxidative stress (Miyata…”

“Its activity is 40–90% lower in AD brains than in control brains, and this reduction correlates with cognitive decline (Perry et al., 1978; Davies, 1979; Wilcock et al., 1982; Sims et al., 1983; Neary et al., 1986; Bierer et al., 1995; Samuel et al., 1997; Cummings, 2000).”

“2) (Masliah et al., 1995b; Buttini et al., 1999, 2000; Hsia et al., 1999; Mucke et al., 2000).”

“ApoE levels in brain tissues were quantitated by Western blot analysis as described previously (Huang et al., 1996, 2001).”

“ApoE is a 34 kDa lipid carrier protein that participates in the maintenance and repair of neurons (Mahley and Huang, 1999).”

“…et al., 1993; Yankner, 1996; Klein et al., 2001), injected into the brain (Geula et al., 1998), or produced in neurons of transgenic mice (Games et al., 1995; Masliah et al., 1996, 2001; Nalbantoglu et al., 1997; Calhoun et al., 1998; Price et al., 1998; Hsia et al., 1999; Mucke et al., 2000).”

“The therapeutic effect of acetylcholinesterase inhibitors during early stages of AD suggests an early impairment of cholinergic functions (Cummings, 2000; Nakano et al., 2001), and there is evidence that the responsiveness to these compounds is influenced by apoE genotype (Farlow et al.”

“As in our mouse models, the differential effects of apoE3 and apoE4 on the development of AD manifestations were apparent primarily during early but not late stages of the aging process (Farrer et al., 1997; Bookheimer et al., 2000; Greenwood et al., 2000; Small et al., 2000; Yaffe et al., 2000; Chapman et al., 2001;…”

“ApoE3 and apoE4 singly transgenic mice show similar levels and distributions of human apoE in the brain (Raber et al., 1998; Buttini et al., 1999), and 6-month-old hAPP/apoE3 and hAPP/apoE4 mice have comparable levels of A 1–42 and A 1–x (approximates total A ) in the hippocampus (Raber et al.,…”

“The specificity of this immunostain has been documented previously (Buttini et al., 1999).”

“Studies in human AD cases and in hAPP transgenic mice have demonstrated that AD-related synaptic and functional neuronal deficits correlate better with levels of nondeposited A than with plaque load (Holcomb et al., 1999; Hsia et al., 1999; Lue et al., 1999; McLean et al., 1999; Mucke et al., 2000; Raber et al., 2000).”

“This finding may be consistent with the notion that the formation of neurotoxic A species depends on the association of A with “pathological molecular chaperones,” such as apoE and apoJ (Wisniewski and Frangione, 1992; Oda et al., 1995; Ma et al., 1996; Permanne et al., 1997).”

“Previous studies of hAPP/apoE transgenic mice focused primarily on amyloid deposition and plaque-related pathology (Holtzman et al., 1999, 2000a,b) but did not examine effects of human apoE isoforms on other AD-related deficits, such as loss of SYN-IR presynaptic terminals, ChAT activity, or…”

“…et al., 1993; Yankner, 1996; Klein et al., 2001), injected into the brain (Geula et al., 1998), or produced in neurons of transgenic mice (Games et al., 1995; Masliah et al., 1996, 2001; Nalbantoglu et al., 1997; Calhoun et al., 1998; Price et al., 1998; Hsia et al., 1999; Mucke et al., 2000).”

“…of the disease, and their modification by apoE isoforms remains controversial (Poirier et al., 1995; Soininen et al., 1995; Allen et al., 1997; Arendt et al., 1997; Salehi et al., 1998; Gilmor et al., 1999; Bronfman et al., 2000; Corey-Bloom et al., 2000; Tiraboschi et al., 2000; Sjögren et…”

“Its activity is 40–90% lower in AD brains than in control brains, and this reduction correlates with cognitive decline (Perry et al., 1978; Davies, 1979; Wilcock et al., 1982; Sims et al., 1983; Neary et al., 1986; Bierer et al., 1995; Samuel et al., 1997; Cummings, 2000).”

“…extension (Nathan et al., 1994; Holtzman and Fagan, 1998) and synapse formation (Mauch et al., 2001), stabilization of microtubules (Strittmatter et al., 1994; Nathan et al., 1995) and endosomal–lysosomal membranes (Ji et al., 2002), and protection against oxidative stress (Miyata and Smith, 1996).”

“…et al., 1993; Yankner, 1996; Klein et al., 2001), injected into the brain (Geula et al., 1998), or produced in neurons of transgenic mice (Games et al., 1995; Masliah et al., 1996, 2001; Nalbantoglu et al., 1997; Calhoun et al., 1998; Price et al., 1998; Hsia et al., 1999; Mucke et al., 2000).”

“It is expressed at high levels in the brain and can be produced by diverse cell types, including neurons, astrocytes, and microglia (Boyles et al., 1985; Stone et al., 1997; Buttini et al., 1999; Xu et al., 1999, 2000; Dekroon and Armati, 2001).”

“ApoE3 and apoE4 have differential effects on A -dependent memory deficits in hAPP/apoE transgenic mice well before these mice develop amyloid deposits (Raber et al., 2000).”

“…lack of murine apoE or expression of human A in the presence of murine apoE is also associated with age-dependent synaptic and cholinergic deficits (Games et al., 1995; Gordon et al., 1995; Masliah et al., 1995a,b, 1996, 2001; Buttini et al., 1999, 2000; Hsia et al., 1999; Mucke et al., 2000).”

“Studies of AD brains have identified a higher plaque burden in people with apoE4 than in people with apoE3 (Berr et al., 1994; Heinonen et al., 1995; Hyman et al., 1995; Ishii et al., 1997; Johnson et al., 1998; McNamara et al., 1998), and these observations have been confirmed in transgenic models…”

“ChAT activity in the medial septum of 3–10 mice per genotype was determined by previously described procedures (Yeo et al., 1997).”

“The therapeutic effect of acetylcholinesterase inhibitors during early stages of AD suggests an early impairment of cholinergic functions (Cummings, 2000; Nakano et al., 2001), and there is evidence that the responsiveness to these compounds is influenced by apoE genotype (Farlow et al., 1998).”

“Recent findings suggest that endogenous androgens protect singly transgenic male mice against apoE4-dependent behavioral deficits, and that this protection is relative rather than absolute (Raber et al., 2002).”

“It is expressed at high levels in the brain and can be produced by diverse cell types, including neurons, astrocytes, and microglia (Boyles et al., 1985; Stone et al., 1997; Buttini et al., 1999; Xu et al., 1999, 2000; Dekroon and Armati, 2001).”

“…extension (Nathan et al., 1994; Holtzman and Fagan, 1998) and synapse formation (Mauch et al., 2001), stabilization of microtubules (Strittmatter et al., 1994; Nathan et al., 1995) and endosomal–lysosomal membranes (Ji et al., 2002), and protection against oxidative stress (Miyata and Smith, 1996).”

“We focused our analysis on SYN-IR presynaptic terminals, choline acetyltransferase (ChAT) activity, and cholinergic fibers, because decreases in these parameters correlate well with cognitive decline in AD (Terry et al., 1991; Samuel et al., 1997; Sze et al., 1997; Brown et al., 1998).”

“…have been detected primarily in later stages of the disease, and their modification by apoE isoforms remains controversial (Poirier et al., 1995; Soininen et al., 1995; Allen et al., 1997; Arendt et al., 1997; Salehi et al., 1998; Gilmor et al., 1999; Bronfman et al., 2000; Corey-Bloom et al.,…”

“However, it could also reflect the gain of an adverse activity that counteracts or interferes with beneficial activities of the holoprotein (Raber et al., 1998, 2000; Tolar et al., 1999; Buttini et al., 2000; Huang et al., 2001).”

“Because synaptic deficits correlate well with the development of cognitive deficits in AD (DeKosky and Scheff, 1990; Terry et al., 1991; Langlais et al., 1993; Samuel et al., 1997; Sze et al., 1997; Brown et al., 1998), the differential effects of apoE3 and apoE4 identified here might relate…”

“…al., 1998; McNamara et al., 1998; Holtzman et al., 2000a,b) but also in their capacity to protect the brain against diverse injuries, including those elicited by excitotoxins, ischemia, and trauma (E3 E4) (Sheng et al., 1998; Buttini et al., 1999, 2000; Horsburgh et al., 2000; Sabo et al., 2000).”

“The 112Cys3Arg substitution, which differentiates apoE4 from apoE3, affects many aspects of apoE, including its conformation, stability, and binding to lipids and other molecules (Dong and Weisgraber, 1996; Ji et al., 1998; Huang et al., 2001; Raffaı̈ et al., 2001).”

“…effects of apoE3 and apoE4 on the development of AD manifestations were apparent primarily during early but not late stages of the aging process (Farrer et al., 1997; Bookheimer et al., 2000; Greenwood et al., 2000; Small et al., 2000; Yaffe et al., 2000; Chapman et al., 2001; Reiman et al., 2001).”

“In humans, apoE occurs in three major isoforms, which are associated with different risks of developing AD (E4 E3 E2) (Corder et al., 1993; Farrer et al., 1997).”

“However, biochemical and neuropathological alterations of the cholinergic system have been detected primarily in later stages of the disease, and their modification by apoE isoforms remains controversial (Poirier et al., 1995; Soininen et al., 1995; Allen et al., 1997; Arendt et al., 1997; Salehi et al., 1998; Gilmor…”

“…in their effects on A deposition (E4 E3) (Rebeck et al., 1993; Schmechel et al., 1993; Berr et al., 1994; Heinonen et al., 1995; Hyman et al., 1995; Gearing et al., 1996; Ishii et al., 1997; Johnson et al., 1998; McNamara et al., 1998; Holtzman et al., 2000a,b) but also in their capacity to…”

“…4 alleles but without overt AD revealed decreased brain activity, decreased visual attention, and subtle memory impairments in 4 carriers compared with people with other APOE alleles (Caselli et al., 1999; Bookheimer et al., 2000; Greenwood et al., 2000; Small et al., 2000; Reiman et al., 2001).”

“This finding may be consistent with the notion that the formation of neurotoxic A species depends on the association of A with “pathological molecular chaperones,” such as apoE and apoJ (Wisniewski and Frangione, 1992; Oda et al., 1995; Ma et al., 1996; Permanne et al., 1997).”

“…al., 1998; McNamara et al., 1998; Holtzman et al., 2000a,b) but also in their capacity to protect the brain against diverse injuries, including those elicited by excitotoxins, ischemia, and trauma (E3 E4) (Sheng et al., 1998; Buttini et al., 1999, 2000; Horsburgh et al., 2000; Sabo et al., 2000).”

“2) (Masliah et al., 1995b; Buttini et al., 1999, 2000; Hsia et al., 1999; Mucke et al., 2000).”

“…in later stages of the disease, and their modification by apoE isoforms remains controversial (Poirier et al., 1995; Soininen et al., 1995; Allen et al., 1997; Arendt et al., 1997; Salehi et al., 1998; Gilmor et al., 1999; Bronfman et al., 2000; Corey-Bloom et al., 2000; Tiraboschi et…”

“…have identified a higher plaque burden in people with apoE4 than in people with apoE3 (Berr et al., 1994; Heinonen et al., 1995; Hyman et al., 1995; Ishii et al., 1997; Johnson et al., 1998; McNamara et al., 1998), and these observations have been confirmed in transgenic models expressing these…”

“…al., 1998; McNamara et al., 1998; Holtzman et al., 2000a,b) but also in their capacity to protect the brain against diverse injuries, including those elicited by excitotoxins, ischemia, and trauma (E3 E4) (Sheng et al., 1998; Buttini et al., 1999, 2000; Horsburgh et al., 2000; Sabo et al., 2000).”

“ApoE4 increases the plaque burden not only in people with AD but also in nondemented individuals (Berr et al., 1994), underlining the potential dissociation between its effects on amyloid deposition and AD risk/onset.”

“…development of cognitive deficits in AD (DeKosky and Scheff, 1990; Terry et al., 1991; Langlais et al., 1993; Samuel et al., 1997; Sze et al., 1997; Brown et al., 1998), the differential effects of apoE3 and apoE4 identified here might relate closely to the effects of these isoforms on AD risk (E4…”

“As in our mouse models, the differential effects of apoE3 and apoE4 on the development of AD manifestations were apparent primarily during early but not late stages of the aging process (Farrer et al., 1997; Bookheimer et al., 2000; Greenwood et al., 2000; Small et al., 2000; Yaffe et al., 2000; Chapman et al., 2001;…”

“This finding may be consistent with the notion that the formation of neurotoxic A species depends on the association of A with “pathological molecular chaperones,” such as apoE and apoJ (Wisniewski and Frangione, 1992; Oda et al., 1995; Ma et al., 1996; Permanne et al., 1997).”

“…relatively little impact on the severity and progression of neuronal deficits in old age and during later stages of AD (Farrer et al., 1997; Bookheimer et al., 2000; Greenwood et al., 2000; Small et al., 2000; Yaffe et al., 2000; Caselli et al., 2001; Chapman et al., 2001; Reiman et al., 2001).”

“…et al., 1993; Berr et al., 1994; Heinonen et al., 1995; Hyman et al., 1995; Gearing et al., 1996; Ishii et al., 1997; Johnson et al., 1998; McNamara et al., 1998; Holtzman et al., 2000a,b) but also in their capacity to protect the brain against diverse injuries, including those elicited…”

“However, biochemical and neuropathological alterations of the cholinergic system have been detected primarily in later stages of the disease, and their modification by apoE isoforms remains controversial (Poirier et al., 1995; Soininen et al., 1995; Allen et al., 1997; Arendt et al., 1997; Salehi et al., 1998; Gilmor…”

“Studies of AD brains have identified a higher plaque burden in people with apoE4 than in people with apoE3 (Berr et al., 1994; Heinonen et al., 1995; Hyman et al., 1995; Ishii et al., 1997; Johnson et al., 1998; McNamara et al., 1998), and these observations have been confirmed in transgenic models…”

“However, biochemical and neuropathological alterations of the cholinergic system have been detected primarily in later stages of the disease, and their modification by apoE isoforms remains controversial (Poirier et al., 1995; Soininen et al., 1995; Allen et al., 1997; Arendt et al., 1997; Salehi et al., 1998; Gilmor…”

“ApoE levels in brain tissues were quantitated by Western blot analysis as described previously (Huang et al., 1996, 2001).”

“However, biochemical and neuropathological alterations of the cholinergic system have been detected primarily in later stages of the disease, and their modification by apoE isoforms remains controversial (Poirier et al., 1995; Soininen et al., 1995; Allen et al., 1997; Arendt et al., 1997; Salehi et al., 1998; Gilmor…”

“…plaque burden in people with apoE4 than in people with apoE3 (Berr et al., 1994; Heinonen et al., 1995; Hyman et al., 1995; Ishii et al., 1997; Johnson et al., 1998; McNamara et al., 1998), and these observations have been confirmed in transgenic models expressing these human apoE isoforms in…”

“…of apoE3 that might allow it to delay age- and A -dependent synaptic deficits include promotion of neurite extension (Nathan et al., 1994; Holtzman and Fagan, 1998) and synapse formation (Mauch et al., 2001), stabilization of microtubules (Strittmatter et al., 1994; Nathan et al., 1995)…”

“However, biochemical and neuropathological alterations of the cholinergic system have been detected primarily in later stages of the disease, and their modification by apoE isoforms remains controversial (Poirier et al., 1995; Soininen et al., 1995; Allen et al., 1997; Arendt et al., 1997; Salehi et al., 1998; Gilmor…”

“Other studies using transgenic mice that possess different human apoE transgenes also demonstrate an isoform-specific difference (E4>E3) in Aβ deposition (Buttini et al., 2002; Dolev and Michaelson, 2004).”

“Such impairment of synaptic plasticity may account for plaque-independent cognitive failures seen in hAPP transgenic mice (Hsia et al., 1999; Mucke et al., 2000; Buttini et al., 2002; Van Dam et al., 2003), which accumulate oligomers in an age-, region-, and transgenedependent manner (Chang et al.”

“This protection is even seen at 19–24 months of age[6].”

“Further evidence for a key role of soluble Ab in AD pathogenesis came from reports that a cognitive impairment develops well before deposition of insoluble Ab in mice transgenic for human APP (Hsia et al. 1999; Mucke et al. 2000; Buttini et al. 2002).”

“, 2002), neurodegeneration (Buttini et al., 1999; Buttini et al., 2002), androgen receptor deficiency (Raber et al.”

“This effect was prevented by the expression of the ApoE3 allele [41].”

“The dependence of apoE4 fragmentation on the production of apoE in neurons might also explain why NSE-apoE4 mice are susceptible to age-related neurodegeneration (Buttini et al., 1999, 2002), whereas GFAP-apoE4 mice are not (Hartman et al., 2001).”

“The results of our studies add to a growing body of evidence in murine models, suggesting that even before the amyloid deposition in the brain Ab can disrupt neuronal integrity and functions, including synaptic plasticity (Hsia et al, 1999; Buttini et al, 2002).”

“…independently of pathological aggregation of disease-associated proteins (Lambert et al., 1998; Santacruz et al., 2005; Yamamoto et al., 2000), and they can result from synaptic dysfunction rather than neuronal loss (Buttini et al., 2002; Mucke et al., 2000; Walsh et al., 2002; Wang et al., 2002).”

“In several lines of mutant APP transgenic mice, structural changes in presynaptic terminals or neuronal loss are correlated with an increase in A concentration in the brain, but not with plaque load (Hsia et al., 1999; Mucke et al., 2000; Buttini et al., 2002).”

“…deficits (12–15 mo) preceded plaque formation (19–24 mo), and despite Journal of Molecular Neuroscience Volume 23, 2004 their marked difference in plaque loads (>10-fold), old hAPP/apoE4 and hAPP/apoE3 bigenic mice (19–24 mo) had comparable synaptic and cholinergic deficits (Buttini et al., 2002).”

“…differences in brain function have been found in other areas, for example, apoE4 has been found to be less protective against oxidative stress, to affect signaling pathways, and to result in greater cholinergic dysfunction in AD (Buttini et al. 2002; for a review see Cedazo-Minguez 2007).”

“[113] stated that old ApoE-deficient transgenic mice ex-”

“In transgenic (TG) mice overexpressing hAPP/A in neurons, synaptic and behavioral deficits are detectable well before plaque formation (Holcomb et al., 1999; Hsia et al., 1999; Mucke et al., 2000; Raber et al., 2000; Buttini et al., 2002; Westerman et al., 2002; Palop et al., 2003).”

“Journal compilation © 2007 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd A , and the age of the animal, but not on plaque deposition [75].”

“…(Price et al. 1998, Link 2001) have been developed such as: APP transgenic mice (Masliah et al. 1996), ApoE transgenic mice (Buttini et al. 1999, Raber et al., 2000a) and C elegans (Link et al. 2003), tauopathy Drosophila (Wittmann et al. 2001), and also APP þ ApoE mice (Buttini et al. 2002).”

“It is known that A induces not only synaptic disruption but also cholinergic deficits in a mice model of AD [57].”

“More specifically, cell and animal models have observed this detrimental effect in the hippocampus (Holtzman et al., 2000; Buttini et al., 2002; Schmechel et al., 1993; Brecht et al., 2004; Harris et al., 2003; Tesseur et al., 2000).”

“…lysosomal leakage, neurodegeneration, androgen receptor deficiency, and cognitive decline (Tolar et al., 1997, 1999; Raber et al., 1998, 2002; Buttini et al., 1999, 2002; Tesseur et al., 2000; Huang et al., 2001; Ji et al., 2002; Harris et al., 2003, 2004a; Brecht et al., 2004; Chang et al.,…”

“It is interesting to note that the majority of studies reporting cholinergic pathologies were performed in single APP or PS1 mutant mice, which have limited or no Aβ deposition (Hernandez et al., 2001; Jaffar et al., 2001; Boncristiano et al., 2002; Buttini et al., 2002; German et al., 2003; Aucoin et al., 2005; Bales…”

“ApoE4 is associated with progressive synaptic deficits in both AD patients and hAPOE-Tg mouse models [83-87].”

“synapses [100], and show increased deficits in learn-”

“Particularly interesting is the finding that ApoE4 is less neuroprotective than ApoE3 both in vitro and in vivo [9].”

“have also shown that when these mice are crossed with NSE-apoE mice, apoE3 but not apoE4 delays age- and Ah-dependent synaptic and cholinergic deficits and that the mechanism is independent of plaque deposition (Buttini et al., 2002).”

“of human APP display a loss of synaptic density and behavioral phenotypes before amyloid plaques appear in the brain (14-16).”

“Furthermore, the ε4 allele in the temporal lobe has been associated with impaired synaptic activity (Buttini et al., 2002), reduced neurite outgrowth (Sun et al., 1998), more severe Abeta deposition (Tiraboschi et al., 2004; Nagy et al., 1995) and cholinergic deficits (Buttini et al., 2002).”

“deficient for ApoE show a dramatic decrease in fibrillary amyloid deposits [5,6,7,8,9].”

“plaques and tangles) (Buttini et al., 2002) (Mucke et al.”

“…2001), and APOE4 is associated with age-related decreases in synaptophysin-immunoreactive presynaptic terminals, decreased choline acetyltransferase activity, and reduced cholinergic fibers in mutant hAPP mice expressing APOE4 under the direction of neuron-specific enolase (Buttini et al, 2002).”

“These findings are consistent with a sequence of pathologic events whereby amyloid deposit comes prior to tangles in the sequence linking the apolipoprotein E ε4 allele to level of cognition [31,32].”

“Finally, replacement of murine apoE with human apoE2, E3, and E4 leads to isoform-specific differences in amyloid load, with apoE4expressing mice developing the greatest amyloid load and apoE2-expressing mice developing the least [28–31], consistent with the apoE isoform effect on vascular and parenchymal Ab deposits…”

“Thus, evidence based on some AD animal models suggests that any potential deficits within the cholinergic system do not make a primary contribution to the pathophysiology of AD (Buttini et al., 2002; Contestabile et al., 2008; German et al., 2003).”

“Many AD-like features have been reproduced in murine models expressing human ApoE4, including increased plaques (24, 25), reduced presynaptic terminals with ApoE4 (4, 5, 6), increased phosphorylated tau with neuronal expression of ApoE4 (3, 21, 59), and impaired spatial learning and memory (28, 42, 43).”

“…suggests that functional alterations could occur before senile plaque formation, a proposition already sustained by others from molecular, cellular and ⁄ or functional studies (Moechars et al., 1999; Wong et al., 1999; Buttini et al., 2002; Selkoe, 2002; Terwel et al., 2002; Van Dam et al., 2003).”

“Studies in transgenic mice are conflicting, with some reporting a loss of synapses, while others found no change [4,11,12,14,18,27].”