Loss of α7 Nicotinic Receptors Enhances β-Amyloid Oligomer Accumulation, Exacerbating Early-Stage Cognitive Decline and Septohippocampal Pathology in a Mouse Model of Alzheimer's Disease

“…of the holoprotein (CTF- ) are reduced in hippocampus Many lines of evidence suggest a role for soluble oligomeric A species in the pathology of AD (Walsh et al., 2002; Lesné et al., 2006; Kayed et al., 2007; Lacor et al., 2007; Venkitaramani et al., 2007; Glabe, 2008; Poling et al., 2008).”

“…Copyright © 2010 the authors 0270-6474/10/302442-12$15.00/0 cits, impaired synaptic plasticity, and alterations of several biochemical markers (Hsiao et al., 1996; Dineley et al., 2001, 2002a; Apelt et al., 2002; Westerman et al., 2002; Spires et al., 2005; Jacobsen et al., 2006).”

“ChAT activity assays were performed according to the Fonnum method (Fonnum, 1975).”

“…on human AD postmortem tissue indicates that much of the receptor protein is functionally inactivated as a result of association with A peptide (Perry et al., 1978; Banerjee et al., 2000; Martin-Ruiz et al., 2000; Dineley et al., 2001 2002b; Teaktong et al., 2003; Counts et al., 2007; Ren et…”

“…of the holoprotein (CTF- ) are reduced in hippocampus Many lines of evidence suggest a role for soluble oligomeric A species in the pathology of AD (Walsh et al., 2002; Lesné et al., 2006; Kayed et al., 2007; Lacor et al., 2007; Venkitaramani et al., 2007; Glabe, 2008; Poling et al., 2008).”

“…the observed loss of basal ERK activity in A7KO–APP hippocampus may contribute to one or all of the following observations in these mice: learning and memory deficits, loss of cholinergic functionality, and hippocampal neurodegeneration (Sweatt, 2001; Thatcher et al., 2006; Williams et al., 2007).”

“Loss of ERK activity in A7KO–APP hippocampus In addition to its well known role in neuroprotection, the ERK mitogen-activated protein kinase (MAPK) cascade is important for certain hippocampus-dependent learning and memory tasks, including contextual fear conditioning (Atkins et al., 1998).”

“At 5 months of age, A7KO–APP hippocampus contains 60 pmol/g A ; this is approximately sixfold higher than reported for wild-type mice (Kawarabayashi et al., 2001).”

“The time spent exploring a novel object versus a familiar object is a measure of attention and nonspatial declarative memory (Broadbent et al., 2004).”

“…of the holoprotein (CTF- ) are reduced in hippocampus Many lines of evidence suggest a role for soluble oligomeric A species in the pathology of AD (Walsh et al., 2002; Lesné et al., 2006; Kayed et al., 2007; Lacor et al., 2007; Venkitaramani et al., 2007; Glabe, 2008; Poling et al., 2008).”

“…Copyright © 2010 the authors 0270-6474/10/302442-12$15.00/0 cits, impaired synaptic plasticity, and alterations of several biochemical markers (Hsiao et al., 1996; Dineley et al., 2001, 2002a; Apelt et al., 2002; Westerman et al., 2002; Spires et al., 2005; Jacobsen et al., 2006).”

“…Copyright © 2010 the authors 0270-6474/10/302442-12$15.00/0 cits, impaired synaptic plasticity, and alterations of several biochemical markers (Hsiao et al., 1996; Dineley et al., 2001, 2002a; Apelt et al., 2002; Westerman et al., 2002; Spires et al., 2005; Jacobsen et al., 2006).”

“This observation is similar to those made in human postmortem brain in which ChAT activity is upregulated in samples from patients with early AD (DeKosky et al., 2002; Ikonomovic et al., 2003; Counts et al., 2007).”

“Most notably, this is expressed as reduced ChAT activity within hippocampus (Kuo et al., 1996; Tapiola et al., 2000; Andreasen et al., 2003).”

“Because NOR cannot distinguish degrees of cognitive impairment, our next experiments were designed to address whether A7KO–APP have a more severe cognitive deficit than APP.”

“…Copyright © 2010 the authors 0270-6474/10/302442-12$15.00/0 cits, impaired synaptic plasticity, and alterations of several biochemical markers (Hsiao et al., 1996; Dineley et al., 2001, 2002a; Apelt et al., 2002; Westerman et al., 2002; Spires et al., 2005; Jacobsen et al., 2006).”

“Whereas 7 nAChR knock-out (A7KO) mice neither show cognitive deficits nor exhibit morphological CNS abnormalities, we found that cognitive deficits seen in 5-month-old APP transgenic mice are more severe when 7 nAChR receptors are absent (A7KO–APP) (Orr-Urtreger et al., 1997; Paylor et al., 1998).”

“For the detection of all other proteins, see Dineley et al. (2001) for more detail.”

“…-amyloid (A ) toxicity; in vivo, 7 nAChRs have been shown to maintain the septohippocampal cholinergic phenotype, suggesting that 7 nAChR activation represents a useful therapeutic strategy for AD (Jonnala and Buccafusco, 2001; Kihara et al., 2001, 2004; Li et al., 2005; Ren et al., 2007).”

“The 7 subtype of nAChR is expressed by basal forebrain cholinergic projection neurons and within the hippocampus (Hunt and Schmidt, 1978; Fabian-Fine et al., 2001; Azam et al., 2003).”

“…inactivated as a result of association with A peptide (Perry et al., 1978; Banerjee et al., 2000; Martin-Ruiz et al., 2000; Dineley et al., 2001 2002b; Teaktong et al., 2003; Counts et al., 2007; Ren et al., 2007; Soderman et al., 2008; Ikonomovic et al., 2009; Wang et al., 2009; Yu et al., 2009).”

“Previous studies on APP mice have failed to detect robust deficits in synaptophysin at any age, and MAP2 decline has only been reported for aged APP animals (9 –24 months old) (Savage et al., 2002; Fonseca et al., 2004).”

“Soluble, fibrillar, oligomeric A has recently been implicated in correlating most strongly with cognitive status in mild cognitive impairment and early AD (Tomic et al., 2009).”

“…versus somatodendritic 7 nAChRs differentially contribute to neuroprotection or neurotoxicity because there is evidence that A activates presynaptic 7 nAChRs, whereas much evidence suggests that A blocks somatodendritic 7 nAChRs (Liu et al., 2001; Pettit et al., 2001; Dougherty et al., 2003).”

“Several studies have demonstrated that nAChR activation attenuates Aβ toxicity and promotes the integrity of the cholinergic phenotype; protection from Aβ toxicity is proportional to the number of α7 nAChRs expressed by cells (Jonnala and Buccafusco, 2001) (Kihara et al., 1997).”

“In contrast, hippocampal ACh neurotransmission is an essential component during the acquisition and retrieval phases of context-dependent learning such as fear conditioning and NOR (Scali et al., 1997; Nail-Boucherie et al., 2000; Sanders et al., 2003; Rogers and Kesner, 2004; Winters et al., 2008).”

“Likewise, as was reported previously by Paylor et al. (1998), 7 null mice did not exhibit any deficits in contextual learning.”

“Previous studies on APP mice have failed to detect robust deficits in synaptophysin at any age, and MAP2 decline has only been reported for aged APP animals (9 –24 months old) (Savage et al., 2002; Fonseca et al., 2004).”

“…versus somatodendritic 7 nAChRs differentially contribute to neuroprotection or neurotoxicity because there is evidence that A activates presynaptic 7 nAChRs, whereas much evidence suggests that A blocks somatodendritic 7 nAChRs (Liu et al., 2001; Pettit et al., 2001; Dougherty et al., 2003).”

“However, cholinergic hypofunction and marked hippocampal neurodegeneration are noticeably absent (Apelt et al., 2002; Stein and Johnson, 2002; Lüth et al., 2003; Wenk et al., 2004; Watanabe et al., 2009).”

“…evaluated for general health, sensory perceptiveness, activity level, as well as object recognition and associative learning performance at 5 months of age according to our previously published methods (Dineley et al., 2002b, 2007; Taglialatela et al., 2009) with some modifications as described.”

“Thus, in early AD, 7 nAChRs serve a neuroprotective role through both receptor activation and harboring oligomeric A away from additional toxic interactions (Walsh et al., 2002, 2005).”

“Animals were evaluated for general health, sensory perceptiveness, activity level, as well as object recognition and associative learning performance at 5 months of age according to our previously published methods (Dineley et al., 2002b, 2007; Taglialatela et al., 2009) with some modifications as described.”

“2b) (Corcoran et al., 2002; Dineley et al., 2002b, 2007; Comery et al., 2005).”

“…evaluated for general health, sensory perceptiveness, activity level, as well as object recognition and associative learning performance at 5 months of age according to our previously published methods (Dineley et al., 2002b, 2007; Taglialatela et al., 2009) with some modifications as described.”

“…and A accumulation may also depend on the APP sequence itself because A accumulation in the PDAPP mouse model expressing a different APP mutant (containing both the “Swedish” and “Indiana” mutations) did not exhibit any differences in APP processing or A levels (Dziewczapolski et al., 2009).”

“…at 25 m. Sections were deparaffinized (if needed) and rehydrated and then stained with 0.5% cresyl violet or immunostained with anti-neuronal nuclear antigen (NeuN); in the case of aged samples, sections were also stained with 0.2% Congo Red (Paxinos and Watson, 2003; Wilcock et al., 2006).”

“Most notably, this is expressed as reduced ChAT activity within hippocampus (Kuo et al., 1996; Tapiola et al., 2000; Andreasen et al., 2003).”

“Future studies will evaluate additional cell populations in hippocampus that are enriched for 7 nAChRs such as interneurons (e.g., GAD67 positive) and glia (e.g., GFAP and S100 positive) (Khiroug et al., 2003; Teaktong et al., 2003).”

“As was previously measured in Tg2576 mice, freezing to the context 24 hours following 2-pair training for fear conditioning was impaired in the APP mice (Figure 2b; Corcoran et al., 2002; Dineley et al., 2002b; Comery et al., 2005; Dineley et al., 2007).”

“The 7 subtype of nAChR is expressed by basal forebrain cholinergic projection neurons and within the hippocampus (Hunt and Schmidt, 1978; Fabian-Fine et al., 2001; Azam et al., 2003).”

“This observation is similar to those made in human postmortem brain in which ChAT activity is upregulated in samples from patients with early AD (DeKosky et al., 2002; Ikonomovic et al., 2003; Counts et al., 2007).”

“As was previously measured in Tg2576 mice, freezing to the context 24 hours following 2-pair training for fear conditioning was impaired in the APP mice (Figure 2b; Corcoran et al., 2002; Dineley et al., 2002b; Comery et al., 2005; Dineley et al., 2007).”

“…-amyloid (A ) toxicity; in vivo, 7 nAChRs have been shown to maintain the septohippocampal cholinergic phenotype, suggesting that 7 nAChR activation represents a useful therapeutic strategy for AD (Jonnala and Buccafusco, 2001; Kihara et al., 2001, 2004; Li et al., 2005; Ren et al., 2007).”

“Several studies have demonstrated that α7 nAChR activation attenuates Aβ toxicity; in vivo, α7 nAChRs have been shown to maintain the septo-hippocampal cholinergic phenotype suggesting that α7 nAChR activation represents a useful therapeutic strategy for AD (Jonnala and Buccafusco, 2001; Kihara et al., 2001; Kihara et…”

“, GFAPand S100β- positive) (Teaktong et al., 2003;Khiroug et al., 2003).”

“Most notably, this is expressed as reduced ChAT activity within hippocampus (Kuo et al., 1996; Tapiola et al., 2000; Andreasen et al., 2003).”

“, 1987), which appear to be via reductions in choline acetyltransferase (ChAT) activity as well as depletion of nicotinic acetylcholine receptors (nAChRs)(Perry et al., 1978; Banerjee et al., 2000; Pappas et al., 2000).”

“The 7 subtype of nAChR is expressed by basal forebrain cholinergic projection neurons and within the hippocampus (Hunt and Schmidt, 1978; Fabian-Fine et al., 2001; Azam et al., 2003).”

“…of the holoprotein (CTF- ) are reduced in hippocampus Many lines of evidence suggest a role for soluble oligomeric A species in the pathology of AD (Walsh et al., 2002; Lesné et al., 2006; Kayed et al., 2007; Lacor et al., 2007; Venkitaramani et al., 2007; Glabe, 2008; Poling et al., 2008).”

“In addition to Aβ over-production and accumulation, this animal model exhibits early onset (5-months-ofage) and progressive memory deficits, impaired synaptic plasticity, and alterations of several biochemical markers (Hsiao et al., 1996; Dineley et al., 2001; Apelt et al., 2002; Dineley et al., 2002a; Westerman et al…”

“…inactivated as a result of association with A peptide (Perry et al., 1978; Banerjee et al., 2000; Martin-Ruiz et al., 2000; Dineley et al., 2001 2002b; Teaktong et al., 2003; Counts et al., 2007; Ren et al., 2007; Soderman et al., 2008; Ikonomovic et al., 2009; Wang et al., 2009; Yu et al., 2009).”

“We have shown previously that soluble oligomeric A , composed mainly of trimers and hexamers, activates ERK MAPK via 7 nAChRs (Dineley et al., 2001; Bell et al., 2004).”

“In contrast, hippocampal ACh neurotransmission is an essential component during the acquisition and retrieval phases of context-dependent learning such as fear conditioning and NOR (Scali et al., 1997; Nail-Boucherie et al., 2000; Sanders et al., 2003; Rogers and Kesner, 2004; Winters et al., 2008).”

“…inactivated as a result of association with A peptide (Perry et al., 1978; Banerjee et al., 2000; Martin-Ruiz et al., 2000; Dineley et al., 2001 2002b; Teaktong et al., 2003; Counts et al., 2007; Ren et al., 2007; Soderman et al., 2008; Ikonomovic et al., 2009; Wang et al., 2009; Yu et al., 2009).”

“Because NOR cannot distinguish degrees of cognitive impairment, our next experiments were designed to address whether A7KO–APP have a more severe cognitive deficit than APP.”

“, 1987), which appear to be via reductions in choline acetyltransferase (ChAT) activity as well as depletion of nicotinic acetylcholine receptors (nAChRs)(Perry et al., 1978; Banerjee et al., 2000; Pappas et al., 2000).”

“Animals that spent 7 s exploring the objects during the 10 min test session were omitted from analysis (de Bruin and Pouzet, 2006).”

“The optical fractionator technique was used to estimate neuronal numbers and the Cavalieri principal to determine hippocampal subfield layer volumes as described by Bonthius et al. (2004).”

“However, cholinergic hypofunction and marked hippocampal neurodegeneration are noticeably absent (Apelt et al., 2002; Stein and Johnson, 2002; Lüth et al., 2003; Wenk et al., 2004; Watanabe et al., 2009).”

“…of the holoprotein (CTF- ) are reduced in hippocampus Many lines of evidence suggest a role for soluble oligomeric A species in the pathology of AD (Walsh et al., 2002; Lesné et al., 2006; Kayed et al., 2007; Lacor et al., 2007; Venkitaramani et al., 2007; Glabe, 2008; Poling et al., 2008).”

“In contrast, hippocampal ACh neurotransmission is an essential component during the acquisition and retrieval phases of context-dependent learning such as fear conditioning and NOR (Scali et al., 1997; Nail-Boucherie et al., 2000; Sanders et al., 2003; Rogers and Kesner, 2004; Winters et al., 2008).”

“However, this view is confounded by the fact that 7 nAChRs and A peptides have been shown to interact in vitro and in vivo, including human postmortem AD brain (Dineley, 2007; Wang et al., 2009).”

“…inactivated as a result of association with A peptide (Perry et al., 1978; Banerjee et al., 2000; Martin-Ruiz et al., 2000; Dineley et al., 2001 2002b; Teaktong et al., 2003; Counts et al., 2007; Ren et al., 2007; Soderman et al., 2008; Ikonomovic et al., 2009; Wang et al., 2009; Yu et al., 2009).”

“, 2009); (Perry et al., 1978; Banerjee et al., 2000; Martin-Ruiz et al., 2000; Dineley et al., 2001; Dineley et al., 2002b; Teaktong et al., 2003; Counts et al., 2007; Ikonomovic et al., 2009; Yu et al., 2009).”

“Previous work on an APP mouse model found impaired cholinergic neurotransmission in the cortex and hippocampus but not the basal forebrain of 19-21 -month-old animals (Apelt et al., 2002; Luth et al., 2003).”

“Soluble oligomeric assemblies of A were analyzed in hippocampal tissue from WT, A7KO, APP, and A7KO–APP animals using immunoblot with OC antibody, selective for fibrillar oligomeric amyloid structures (Kayed et al., 2007; Glabe, 2008).”

“…the observed loss of basal ERK activity in A7KO–APP hippocampus may contribute to one or all of the following observations in these mice: learning and memory deficits, loss of cholinergic functionality, and hippocampal neurodegeneration (Sweatt, 2001; Thatcher et al., 2006; Williams et al., 2007).”

“A interaction has also been suspected in mediating A toxicity (Dineley, 2007; Ren et al., 2007; Clifford et al., 2008; Soderman et al., 2008; Wang et al., 2009).”

“Thus the observed loss of basal ERK activity in A7KO-APP hippocampus may contribute to one or all of the following observations in these mice: learning and memory deficits, loss of cholinergic functionality, and hippocampal neurodegeneration (Sweatt, 2001; Thatcher et al., 2006; Williams et al., 2007).”

“Genotype of each animal was determined by PCR of genomic DNA isolated from tail biopsy material obtained at weaning (Orr-Urtreger et al., 1995, 1997; Hsiao et al., 1996).”

“Several studies have demonstrated that α7 nAChR activation attenuates Aβ toxicity; in vivo, α7 nAChRs have been shown to maintain the septo-hippocampal cholinergic phenotype suggesting that α7 nAChR activation represents a useful therapeutic strategy for AD (Jonnala and Buccafusco, 2001; Kihara et al., 2001; Kihara et…”

“However, cholinergic hypofunction and marked hippocampal neurodegeneration are noticeably absent (Apelt et al., 2002; Stein and Johnson, 2002; Lüth et al., 2003; Wenk et al., 2004; Watanabe et al., 2009).”

“In an early AD mouse model, a7 nAChRs also provided neuroprotection through the maintenance of the septo-hippocampal cholinergic phenotype, the preservation of hippocampal integrity, and decreasing the Ab accumulation and oligomerization (Hernandez et al., 2010).”

“Two examples from the literature showed strikingly opposite outcomes (Dziewczapolski et al., 2009; Hernandez et al., 2010).”