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).”

“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).”

“…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).”

“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.”

“…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).”

“…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).”

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

“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…”

“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).”

“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).”

“…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).”

“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).”

“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).”

“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).”

“…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).”

“…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).”

“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).”

“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).”

“The α7NRs are involved in cognitive function and may be underactive in schizophrenia (Breese et al., 2000; Mexal et al., 2010), while their deletion has profoundly negative consequences for learning and memory (Hernandez et al., 2010).”

“In transgenic animals, overexpressing Ab beneficial effects of nicotine or ChE-I were indeed observed, while knock out of the a7 nAChR worsened pathology [12, 62, 220].”

“, 1996) provides a model of AD-like pathology, including accumulation of A peptides, plaque deposition, and cognitive deficits that worsen with age (Dineley et al., 2002; Westerman et al., 2002; Hernandez et al., 2010).”

“In model systems, oligomers are more toxic and correlate with cognitive impairments in AD mouse models (Lesné et al., 2006; Cheng et al., 2007; Hernandez et al., 2010), and humans (Tomic et al.”

“Nonetheless, the neuroprotective role of nAChRs by counterbalancing the toxicity of Aβ oligomers has been proposed based on experimental observation [109].”

“The apparent contradictory observation of an exacerbation of AD effects in a7 nAChR knockout mice (Hernandez et al., 2010) versus improvement observed in another model (Dziewczapolski et al., 2009) can be reconciled when considering the stage and conditions.”

“This explanation may also justify contradictory findings in animal studies, where transgenic AD mice deficient in α7nChR expression exhibited exacerbated AD pathology in one report [92] and ameliorated pathology in another [93].”

“Guangdong 515041, People’s Republic of China jxshen@stu.edu.cn mouse model decreases (Dziewczapolski et al. 2009) or enhances (Hernandez et al. 2010) cognitive deficits associated with AD.”

“Importantly our study shows that Aβ1-42 levels are elevated in the first two postnatal weeks, long before synaptic and cognitive deficits can be detected [13,36,37] at 5-6 months and coincide with insoluble Aβ1-42 deposition [48,49].”

“Recently, it was shown that the loss of α7nAChR in Tg2576 mice (A7KO-APP mice) enhances Aβ oligomer accumulation in the extracellular space and increases early cognitive decline and septohippocampal pathology in young animals [109], but improves cognitive deficits and synaptic pathology in aged A7KO-APP mice [110].”

“On the other hand, Targeting α7 nAChR has been suggested to reduce microglia activation and enhance the ability to clear the misfolded and aggregated proteins (Hernandez et al., 2010; Takata et al., 2010; Medeiros et al., 2014).”

“Further loss of α7 nicotinic acetylcholine receptors leads to enhanced β-amyloid oligomer accumulation in mouse model of Alzheimer's disease (Hernandez et al., 2010).”

“and cognitive processes associated with learning and memory (Voytko et al., 1994; Hernandez et al., 2010).”

“…α7 nAChR in the hippocampus results in significant learning and memory impairments (Levin et al., 2002; Fernandes et al., 2006; Nott & Levin, 2006; Young et al., 2007; Levin et al., 2009), and worsens the learning and memory deficits in a mouse model of Alzheimer’s disease (Hernandez et al., 2010).”

“Indeed, A actions via 7 nAChRs may also affect hippocampal LTP (Gu and Yakel, 2011), and genetic depletion of 7 nAChRs in an early-stage AD mouse model exacerbated cognitive deficits and septohippocampal pathology (Hernandez et al., 2010).”

“Tg2576 also do not portray overt neurodegeneration yet Tg2576 exhibit synapse and volume loss in the hippocampus (Hernandez et al., 2010; Irizarry et al., 1997) which is considered one of the best correlates to cognitive impairment of early, and possibly preclinical, AD (Albert et al., 2011;…”

“, 2009), and worsens the learning and memory deficits in a mouse model of Alzheimer’s disease (Hernandez et al., 2010).”

“Tg2576 mice show deficits in the NOR memory task (Hernandez et al., 2010).”

“However, 7-nAChRmediated effects may critically depend on animal age (and perhaps background), because one recent study (Hernandez et al., 2010), using a mouse model of AD, suggests that deletion of 7 subunits exacerbates learning deficits in young animals and alters the pattern of A accumulation.”

“The α7 nAChR subtype is known to be involved in the Aβ processing and metabolism [24].”

“This discrepancy is explained by Hernandez et al. (2010) as a difference in the age of the animals used; the α7 nAChR activity appears to be neuroprotective in early Alzheimer’s disease, whereas it may be deleterious in later stages of Alzheimer’s disease (Dziewczapolski et al. 2009; Hernandez et…”

“Alternatively, several studies showed degeneration of the cholinergic system inoldADmodelmice (Devi andOhno, 2010;Hernandez et al., 2010; Perez et al., 2011), and activation of 5-HT4 receptors is known to increase acetylcholine levels (Consolo et al., 1994; Yamaguchi et al., 1997a; Yamaguchi et…”

“Several lines of research point to a central role for the a7 nAChR in the etiology of AD (Wang et al., 2000; Dineley et al., 2002; Chen et al., 2006; Counts et al., 2007; Dziewczapolski et al., 2009; Hernandez et al., 2010; Heinzen et al., 2010; also reviewed in Bencherif and Lippiello, 2011).”

“The activation of α7nAChR attenuates Aβ toxicity by a high affinity interaction with the Aβ peptide and as such retards the oligomerization of Aβ peptides [29].”

“However, conflicting research showed that loss of α7nAChR in an AD mouse model enhanced Aβ oligomer accumulation and exacerbated cognitive decline and septohippocampal pathology (Hernandez et al., 2010).”

“Further, loss of a7 nicotinic acetylcholine receptors leads to increased b-amyloid oligomer accumulation in mouse model of AD [27].”

“However, it is also reported that loss of a7 nAChRs enhanced beta-amyloid oligomer accumulation and exacerbated early stage cognitive decline in a mouse model of AD (Hernandez et al., 2010).”

“Tg2576 also do not portray overt neurode-generation yet Tg2576 exhibit synapse and volume loss in the hippocampus [147, 172] which is consid-eredoneofthebestcorrelatestocognitiveimpairmentofearly,andpossiblypreclinical,AD[8,9,44, 173].”

“demonstrated that memory deficits in neurodegenerative diseases are often characterized by decreased cholinergic terminals in the hippocampus [10,11,23,24,25], which further highlights the role of cholinergic receptors in memory.”

“A loss of α7-nAChR exacerbates early-stage cognitive decline and septohippocampal pathology in a mouse model of AD (Hernandez et al., 2010; Cheng et al., 2015).”

“The cognitive deficits seen in APP transgenic mice worsen when α7 nAChR is absent at the same time [84].”

“This homeostatic response has been proposed to initially protect the system from cognitive decline (Hernandez et al., 2010; Pratt et al., 2011; Small, 2004, 2007) but eventually facilitate later neurodegeration (Small, 2004, 2008).”

“…and tau (3xTg-ADmice) (Oddo et al., 2003; Billings et al., 2005; Kitazawa et al., 2005) were consistent with the aforementioned in vitro conclusions for human AD, demonstrating an age dependent reduction of α7 nAChR, as higher Aβ may eventually block remaining α7 nAChRs (Hernandez et al., 2010).”

“Other evidence indicates that α7 nAChR is involved in memory and cognitive functions and plays a neuroprotective role in AD by influencing the accumulation and oligomerization of Aβ [54, 55].”

“Despite existing evidence about molecular interaction between A β and α 7 nAChRs (Wang et al., 2000), contradictory results have been reported about the contribution of α 7 nAChRs to the pathophysiology of AD (Dziewczapolski et al., 2009; Hernandez et al., 2010).”