Using mice to model Alzheimer's dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models

“Once the AD patient progresses past MCI and into dementia, general cognition continues to decline with deficits appearing in all respective cognitive domains (Huff et al., 1987; Locascio et al., 1995; Lambon Ralph et al., 2003; Mckhann et al., 2011).”

“In this model, the cognitive deficits first present themselves in spatial working memory at 4 months of age when assessed by MWM testing (Hartman et al., 2005).”

“(Promoter: Hamster PrP Promoter, Symbol: Tg (APPSWE) 2576Kha, MGI ID: 2385631) In the Tg2576 mouse (Hsiao et al., 1996), the first presentation of cognitive deficits is seen at 5 months of age in spatial working memory (Arendash et al., 2004).”

“The Alzheimer’s Disease Assessment Scale (ADAS) was specifically developed to measure the severity of symptoms commonly seen in AD (Rosen et al., 1984).”

“…tests are extensively used as clinical diagnostic tools (Schmitt, 1994) as well as to track the progression of the disease (Flicker et al., 1984; Morris et al., 1989; Storandt and Hill, 1989; Storandt, 1991; Welsh et al., 1991, 1992; Locascio et al., 1995; Albert, 1996; Storandt et al., 1998;…”

“…2006), 25: (Ohno et al., 2006), 26: (Shukla et al., 2013), 27: (Devi and Ohno, 2010), 28:(Devi and Ohno, 2012), 29: (Urano and Tohda, 2010), 30: (Oddo et al., 2003), 31: (Clinton et al., 2007), 32: (Carroll et al., 2007), 33: (Gimenez-Llort et al., 2007), 34: (Billings et al., 2005), 35:…”

“There have been numerous clinicopathological studies attempting to correlate amyloid plaques with the cognitive deficits seen in AD (Blessed et al., 1968; Tomlinson et al., 1970; Duyckaerts et al., 1990, 1998; Berg et al., 1998; Gold et al., 2000; Mungas et al., 2001; Tiraboschi et al., 2002, 2004;…”

“(Promoter: Thy-1, Symbol: Tg (APPSwFlLon, PSEN1 ∗ M146L ∗ L286V) 6799Vas, MGI ID: 3693208) The 5 × FAD model, first described by Oakley et al. (2006), develops progressive cognitive deficits with age.”

“First, the strongest correlation between amyloid plaques and cognition is in the early stages of the disease and this association weakens as NFTs and gross neocortical neurodegeneration become more widespread (Thal et al., 2002; Nelson et al., 2009b, 2012).”

“In 2012, new consensus guidelines for neuropathologic evaluation of AD were adopted (Hyman et al., 2012; Montine et al., 2012).”

“In 2012, new consensus guidelines for neuropathologic evaluation of AD were adopted (Hyman et al., 2012; Montine et al., 2012).”

“…is a strong link between neocortical NFTs and cognitive decline (Tomlinson et al., 1970; Duyckaerts et al., 1990, 1997, 1998; Mckee et al., 1991; Arriagada et al., 1992; Bierer et al., 1995; Davis et al., 1995; Dickson et al., 1995; Nagy et al., 1995, 1999; Cummings et al., 1996; Berg et al.,…”

“(Promoter: Platelet-Derived (PDGF) Promoter, Symbol: Tg (APPV717F) 109Ili, MGI ID: 2151935) The PDAPP mouse was first described by Games in 1995 and is considered one of the earliest mouse models of AD (Chartier-Harlin et al., 1991; Games et al., 1995).”

“Another task that can be considered somewhat analogous to the 5-CSRTT is the human Continuous Performance Tests (CPT) of sustained attention (Beck et al., 1956).”

“Second, it appears that density of neuritic plaques correlates more strongly with the cognitive deficits than do “diffuse” amyloid plaques (Mckee et al., 1991; Crystal et al., 1993; Tiraboschi et al., 2004; Nelson et al., 2007a; Braak et al., 2011).”

“The data also support the “Amyloid Cascade Hypothesis”(Karran et al., 2011), a deceptively complex hypothesis which posits that beta-amyloid/plaque pathology kin-dles widespread tau/NFT pathology, with the tau/NFT pathology constituting the more direct cause of the cell loss and synapse elimination underlying clinical…”

“Another commonly used test battery is that of the Short Blessed Test (SBT) which consists of a six-item test designed to identify the cognitive dysfunction seen in AD (Katzman et al., 1983).”

“…plaques, a large number of studies have arrived at a common finding, namely, there is a strong link between neocortical NFTs and cognitive decline (Tomlinson et al., 1970; Duyckaerts et al., 1990, 1997, 1998; Mckee et al., 1991; Arriagada et al., 1992; Bierer et al., 1995; Davis et al., 1995;…”

“First, the strongest correlation between amyloid plaques and cognition is in the early stages of the disease and this association weakens as NFTs and gross neocortical neurodegeneration become more widespread (Thal et al., 2002; Nelson et al., 2009b, 2012).”

“In both the Wisconsin Card Sorting Task in humans and set-shifting tasks in mice, the dorsolateral and orbital prefrontal cortex is critical for successful performance (Weinberger et al., 1986; Berman et al., 1995; Brigman et al., 2005; Bissonette et al., 2008).”

“…applicable tools to study depression in animal models (Seligman et al., 1975; Jolly et al., 1999; Song and Leonard, 2005; Flint and Shifman, 2008; Nestler and Hyman, 2010), very little work has been devoted to determining the range of depressive behavioral symptoms in the commonly used mouse…”

“A more complex maze type task used to test murine spatial working memory is that of the Radial Arm Maze (RAM), consisting of several arms (usually 6–8) radiating outwards from a central platform (Olton and Samuelson, 1976; Olton et al., 1979).”

“A more complex maze type task used to test murine spatial working memory is that of the Radial Arm Maze (RAM), consisting of several arms (usually 6–8) radiating outwards from a central platform (Olton and Samuelson, 1976; Olton et al., 1979).”

“…et al., 2009), 32: (Gortz et al., 2008), 33:(Richter et al., 2008), 34: (Lovasic et al., 2005), 35: (Janus, 2004), 36: (Hanna et al., 2009), 37: (Mucke et al., 2000), 38: (Harris et al., 2010), 39: (Saura et al., 2005), 40: (Simon et al., 2009), 41: (Lustbader et al., 2004), 42: (Cheng et al.,…”

“Clinically, many of the neuropsychological tests that assess working memory rely heavily on the use of verbal tasks (Kaplan et al., 1978; Benedict et al., 1998; Spreen and Strauss, 1998; Delis et al., 2000), employing language as a core construct and thus are not feasible to model using mice.”

“(Promoter: Thy-1, Symbol: Tg (Thy1-APP) 3Somm, MGI ID: 2447146) TheAPP23 mouse model was reported in 1997 (Sturchler-Pierrat et al., 1997).”

“Numerous meta-analysis studies have linked depression and AD (Chen et al., 1999; Charlson and Peterson, 2002; Ownby et al., 2006; Lenoir et al., 2011; Diniz et al., 2013), and several even consider late-life depression a significant risk factor for future development of AD (Butters et al., 2000,…”

“…on episodic-like memory across a number of animal species has suggested otherwise, and several mouse behavioral tasks designed at assessing episodic-like memory have been developed (Clayton and Dickinson, 1998; Clayton et al., 2001; Griffiths and Clayton, 2001; Morris, 2001; Davis et al., 2013a,b).”

“These deficits are seen in the MWM and progress with age of the animal (Janus et al., 2000; Chishti et al., 2001; Gortz et al., 2008; Richter et al., 2008; Ambree et al., 2009).”

“…tasks The animal must shift back and forth between changing rules to successfully obtain a reward Executive function and cognitive flexibility Birrell and Brown, 2000 Reversal learning Adjustment to changes in reward contingency Executive function and working memory Butter, 1969; Bussey…”

“(Promoter: Hamster PrP Promoter, Symbol: Tg (APPSWE) 2576kha, MGI ID: 2385631) × (Platelet-Derived (PDGF), Symbol: Tg (PDGFB-PSEN1M146L) 2Jhd, MGI ID: 2447326) Holcomb described a mouse model in 1998 that has been widely used to study cognitive deficits related to AD (Holcomb et al., 1998).”

“…29: (Urano and Tohda, 2010), 30: (Oddo et al., 2003), 31: (Clinton et al., 2007), 32: (Carroll et al., 2007), 33: (Gimenez-Llort et al., 2007), 34: (Billings et al., 2005), 35: (Nelson et al., 2007b), 36: (Pietropaolo et al., 2008), 37: (Filali et al., 2012), 38: (Arsenault et al., 2011), 39:…”

“…meta-analysis studies have linked depression and AD (Chen et al., 1999; Charlson and Peterson, 2002; Ownby et al., 2006; Lenoir et al., 2011; Diniz et al., 2013), and several even consider late-life depression a significant risk factor for future development of AD (Butters et al., 2000,…”

“The five choice serial reaction time task (5-CSRTT) is a behavioral task that measures the response inhibition component of executive function (5-CSRTT is also used to model aspects of attention, see below section) in mice (Robbins, 2002; Bari et al., 2008; Chudasama, 2011; Romberg et al., 2013a).”

“Response inhibition is required for the appropriate control of an individual’s behavioral actions in response to a stimulus (Robbins, 1996; Humby et al., 1999; Perry and Hodges, 1999; Romberg et al., 2013a).”

“(Promoter: Platelet-Derived (PDGF) Promoter, Symbol: Tg (APPV717F) 109Ili, MGI ID: 2151935) The PDAPP mouse was first described by Games in 1995 and is considered one of the earliest mouse models of AD (Chartier-Harlin et al., 1991; Games et al., 1995).”

“Generally, depressive symptoms precede the onset of AD (Devanand et al., 1996) and usually worsen with the progression of the disease (Mega et al., 1996).”

“…have been well characterized across the lifespan of this mouse model in water based spatial working memory tasks (Lalonde et al., 2005; Park et al., 2006; Cao et al., 2007; Sood et al., 2007; Ding et al., 2008; Volianskis et al., 2010; Zhang et al., 2011; Cramer et al., 2012; Ma et al., 2012).”

“Not all AD cases fall within the standard NFT distribution described by the Braak staging (Hof et al., 1997; Abner et al., 2011; Murray et al., 2011).”

“(Promoter: PrP, Symbol: Tg (PRNP-APPSweInd) 8Dwst, MGI ID: 3589475) TheTgCRND8 model, described by Chishti et al. (2001), exhibits early cognitive impairment that spans across multiple cognitive domains (Chishti et al., 2001).”

“Non-spatial working memory tasks show a similar time course progression, first appearing at 3–5 months of age and persisting across the lifespan (Hsiao et al., 1996; Chapman et al., 1999; King and Arendash, 2002; Lalonde et al., 2003; Ohno et al., 2004).”

“The cognitive deficits in recognition memory do not appear as robust as those in working memory in this model as there are inconsistent reports in the literature (Dodart et al., 1999, 2002; Chen et al., 2000).”

“In the earliest stages of AD (Braak stage I-II), NFTs are restricted to the entorhinal cortex (Braak and Del Tredici, 2011; Braak et al., 2011).”

“It should be noted that most of the AD mouse models are representative of the familial form of AD (FAD) which accounts for only a small percentage of the total AD cases each year (Campion et al., 1999).”

“The numbers within each cell correspond to the following references: 1: (Jankowsky et al., 2001), 2: (Park et al., 2006), 3: (Cramer et al., 2012), 4: (Reiserer et al., 2007), 5:(Cao et al., 2007) 6:(Lalonde et al., 2004), 7: (Volianskis et al., 2010), 8: (Sood et al., 2007), 9: (Zhang et al.,…”

“…several spatial locations (usually 3–5), observe a corresponding stimulus, and then correctly respond Attention, impulsivity, and executive function Carli et al., 1983 Attentional set-shifting tasks The animal must shift back and forth between changing rules to successfully obtain a reward…”

“In the human disease, the earliest AD-related cognitive deficits present themselves as episodic memory impairment during the late preclinical phase of the disease (Backman et al., 2005; Twamley et al., 2006; Bondi et al., 2008).”

“These spatial working memory deficits are generally accepted to be present across the rest of the life span for this model (Hsiao et al., 1996; Westerman et al., 2002; Arendash et al., 2004).”

“…and AD and having a wide range of potentially applicable tools to study depression in animal models (Seligman et al., 1975; Jolly et al., 1999; Song and Leonard, 2005; Flint and Shifman, 2008; Nestler and Hyman, 2010), very little work has been devoted to determining the range of depressive…”

“…memory, semantic memory, working memory, and attention, as well as dysfunction in language, praxis, and executive functioning (Flicker et al., 1984; Baddeley et al., 1986, 1991, 2001; Huff et al., 1987; Knopman and Ryberg, 1989; Hodges et al., 1992; Parasuraman and Nestor, 1993; Hodges and…”

“…tools (Schmitt, 1994) as well as to track the progression of the disease (Flicker et al., 1984; Morris et al., 1989; Storandt and Hill, 1989; Storandt, 1991; Welsh et al., 1991, 1992; Locascio et al., 1995; Albert, 1996; Storandt et al., 1998; Schmitt et al., 2000; Salmon and Bondi, 2009).”

“…et al., 2002; Guillozet et al., 2003; Bennett et al., 2004; Kraybill et al., 2005; Holtzer et al., 2006; Markesbery et al., 2006; Koepsell et al., 2008; Whitwell et al., 2008; Beach et al., 2009; Brayne et al., 2009; Giannakopoulos et al., 2009; Sabbagh et al., 2010; Robinson et al., 2011).”

“These disturbances include hyperactivity, stereotypic behaviors, and home cage activity disturbances (Dodart et al., 1999; Janus and Westaway, 2001; Auld et al., 2002; Dumont et al., 2004; Hyde et al., 2005; Cheng et al., 2007; Gil-Bea et al., 2007; Gimenez-Llort et al., 2007; Pietropaolo et al.,…”

“…Gil-Bea et al., 2007; Pietropaolo et al., 2008; Sanchez-Mejia et al., 2008; Ambree et al., 2009; Cisse et al., 2011; Mori et al., 2013), anxiety (Moechars et al., 1996, 1999; Lalonde et al., 2003, 2004; Gil-Bea et al., 2007; Reiserer et al., 2007; Lassalle et al., 2008; Espana et al., 2010;…”

“Most studies of MCI patients show consistent impairments in verbal recall (Larrieu et al., 2002; Tuokko et al., 2005; Kryscio et al., 2006) and a decline in general memory functioning (Tuokko et al., 2005; Bondi et al., 2008).”

“…to correlate amyloid plaques with the cognitive deficits seen in AD (Blessed et al., 1968; Tomlinson et al., 1970; Duyckaerts et al., 1990, 1998; Berg et al., 1998; Gold et al., 2000; Mungas et al., 2001; Tiraboschi et al., 2002, 2004; Guillozet et al., 2003; Kraybill et al., 2005; Holtzer et…”

“…language, praxis, and executive functioning (Flicker et al., 1984; Baddeley et al., 1986, 1991, 2001; Huff et al., 1987; Knopman and Ryberg, 1989; Hodges et al., 1992; Parasuraman and Nestor, 1993; Hodges and Patterson, 1995; Perry and Hodges, 1999; Salmon et al., 1999; Perry et al., 2000;…”

“…(Flicker et al., 1984; Baddeley et al., 1986, 1991, 2001; Huff et al., 1987; Knopman and Ryberg, 1989; Hodges et al., 1992; Parasuraman and Nestor, 1993; Hodges and Patterson, 1995; Perry and Hodges, 1999; Salmon et al., 1999; Perry et al., 2000; Backman et al., 2001; Lambon Ralph et al., 2003).”

“First, the strongest correlation between amyloid plaques and cognition is in the early stages of the disease and this association weakens as NFTs and gross neocortical neurodegeneration become more widespread (Thal et al., 2002; Nelson et al., 2009b, 2012).”

“In the following section, we will cover several of the most common neuropsychological tests used clinically to assess the mental status and memory disruptions in AD (for more in depth reviews see Perry and Hodges, 1999; Budson and Price, 2005; Bondi et al., 2008; Weintraub et al., 2012).”

“…Tomlinson et al., 1970; Duyckaerts et al., 1990, 1998; Berg et al., 1998; Gold et al., 2000; Mungas et al., 2001; Tiraboschi et al., 2002, 2004; Guillozet et al., 2003; Kraybill et al., 2005; Holtzer et al., 2006; Markesbery et al., 2006; Nelson et al., 2007a, 2009a; Beach et al., 2009;…”

“…al., 2007), 33: (Gimenez-Llort et al., 2007), 34: (Billings et al., 2005), 35: (Nelson et al., 2007b), 36: (Pietropaolo et al., 2008), 37: (Filali et al., 2012), 38: (Arsenault et al., 2011), 39: (Stewart et al., 2011), 40: (Halagappa et al., 2007). working memory tasks starting at 3 months of age.”

“Response inhibition is required for the appropriate control of an individual’s behavioral actions in response to a stimulus (Robbins, 1996; Humby et al., 1999; Perry and Hodges, 1999; Romberg et al., 2013a).”

“…studies have linked depression and AD (Chen et al., 1999; Charlson and Peterson, 2002; Ownby et al., 2006; Lenoir et al., 2011; Diniz et al., 2013), and several even consider late-life depression a significant risk factor for future development of AD (Butters et al., 2000, 2008; Diniz et al., 2013).”

“Generally, depressive symptoms precede the onset of AD (Devanand et al., 1996) and usually worsen with the progression of the disease (Mega et al., 1996).”

“In both the Wisconsin Card Sorting Task in humans and set-shifting tasks in mice, the dorsolateral and orbital prefrontal cortex is critical for successful performance (Weinberger et al., 1986; Berman et al., 1995; Brigman et al., 2005; Bissonette et al., 2008).”

“The exact mechanism that underlies these increased aggressive behaviors is not known but proposed mechanisms deal with dysregulation of different neurotransmitter systems such as serotonin, norepinephrine, dopamine, and GABA (Arsland, 1995; Meltzer et al., 1998).”

“…et al., 1999; Gold et al., 2000; Mungas et al., 2001; Riley et al., 2002; Silver et al., 2002; Tiraboschi et al., 2002; Guillozet et al., 2003; Bennett et al., 2004; Kraybill et al., 2005; Holtzer et al., 2006; Markesbery et al., 2006; Koepsell et al., 2008; Whitwell et al., 2008; Beach et…”

“…(Clinton et al., 2007), 32: (Carroll et al., 2007), 33: (Gimenez-Llort et al., 2007), 34: (Billings et al., 2005), 35: (Nelson et al., 2007b), 36: (Pietropaolo et al., 2008), 37: (Filali et al., 2012), 38: (Arsenault et al., 2011), 39: (Stewart et al., 2011), 40: (Halagappa et al., 2007).…”

“Other examples of non-spatial working memory tasks are operant tasks such as the Delayed Match to Sample (DMTS), Delayed Non-Match to Sample (DNMTS), and Delayed Stimulus Discrimination Task (DSDT) (Dudchenko, 2004; Buccafusco et al., 2008).”

“In many ways, set-shifting tasks are similar to the Wisconsin Card Sorting Task in that they form the gold standard for assessing executive function (Drewe, 1974; Robinson et al., 1980; Arnett et al., 1994).”

“Second, it appears that density of neuritic plaques correlates more strongly with the cognitive deficits than do “diffuse” amyloid plaques (Mckee et al., 1991; Crystal et al., 1993; Tiraboschi et al., 2004; Nelson et al., 2007a; Braak et al., 2011).”

“…tools (Schmitt, 1994) as well as to track the progression of the disease (Flicker et al., 1984; Morris et al., 1989; Storandt and Hill, 1989; Storandt, 1991; Welsh et al., 1991, 1992; Locascio et al., 1995; Albert, 1996; Storandt et al., 1998; Schmitt et al., 2000; Salmon and Bondi, 2009).”

“…al., 2002; Silver et al., 2002; Tiraboschi et al., 2002; Guillozet et al., 2003; Bennett et al., 2004; Kraybill et al., 2005; Holtzer et al., 2006; Markesbery et al., 2006; Koepsell et al., 2008; Whitwell et al., 2008; Beach et al., 2009; Brayne et al., 2009; Giannakopoulos et al., 2009; Sabbagh…”

“…2002; Dumont et al., 2004; Hyde et al., 2005; Cheng et al., 2007; Gil-Bea et al., 2007; Gimenez-Llort et al., 2007; Pietropaolo et al., 2008; Cisse et al., 2011) and have been linked to altered APP metabolism, amyloid levels, and disease progression (Van Someren et al., 1996; Harper et al., 2004).”

“…memory, semantic memory, working memory, and attention, as well as dysfunction in language, praxis, and executive functioning (Flicker et al., 1984; Baddeley et al., 1986, 1991, 2001; Huff et al., 1987; Knopman and Ryberg, 1989; Hodges et al., 1992; Parasuraman and Nestor, 1993; Hodges and…”

“The five choice serial reaction time task (5-CSRTT) is a behavioral task that measures the response inhibition component of executive function (5-CSRTT is also used to model aspects of attention, see below section) in mice (Robbins, 2002; Bari et al., 2008; Chudasama, 2011; Romberg et al., 2013a).”

“…(Flicker et al., 1984; Baddeley et al., 1986, 1991, 2001; Huff et al., 1987; Knopman and Ryberg, 1989; Hodges et al., 1992; Parasuraman and Nestor, 1993; Hodges and Patterson, 1995; Perry and Hodges, 1999; Salmon et al., 1999; Perry et al., 2000; Backman et al., 2001; Lambon Ralph et al., 2003).”

“…mouse include increased locomotor activity (Dodart et al., 1999; King et al., 1999; Arendash et al., 2001b; Dumont et al., 2004; Hyde et al., 2005; Cheng et al., 2007; Gil-Bea et al., 2007; Pietropaolo et al., 2008; Sanchez-Mejia et al., 2008; Ambree et al., 2009; Cisse et al., 2011; Mori et al.,…”

“…from as low as 2% to as high as 85% (variability likely due to methods of assessment, diagnostic criteria, stage of AD participants, and other factors) (Mendez et al., 1990; Burns et al., 1990a; Migliorelli et al., 1995a,b; Devanand et al., 1996; Cummings, 2000; Apostolova and Cummings, 2008).”

“For recent reviews of additional AD mouse strains not included here, see (Ashe and Zahs, 2010; Elder et al., 2010; Epis et al., 2010; Hall and Roberson, 2012; Platt et al., 2013).”

“…changes may show subtle or undetectable cognitive impairment, yet all cases with quantifiably “end stage” neocortical NFT pathology show cognitive impairment (Dickson et al., 1995; Berlau et al., 2007; Nelson et al., 2009a, 2012; Abner et al., 2011; Santacruz et al., 2011; Jicha et al., 2012).”

“Response inhibition is required for the appropriate control of an individual’s behavioral actions in response to a stimulus (Robbins, 1996; Humby et al., 1999; Perry and Hodges, 1999; Romberg et al., 2013a).”

“These spatial working memory deficits are present across the rest of this model’s lifespan (Palop et al., 2003; Galvan et al., 2006; Cisse et al., 2011; Du et al., 2011; Murakami et al., 2011; Fang et al., 2012).”

“…and cognitive flexibility Birrell and Brown, 2000 Reversal learning Adjustment to changes in reward contingency Executive function and working memory Butter, 1969; Bussey et al., 1997 What-Where-Which Task (WWWhich) The animal must associate an object (What) with its location (Where) in a…”

“In many ways, set-shifting tasks are similar to the Wisconsin Card Sorting Task in that they form the gold standard for assessing executive function (Drewe, 1974; Robinson et al., 1980; Arnett et al., 1994).”

“Increased aggressive behaviors are another common behavioral symptom of AD and present themselves in as much as 65% of AD patients (Burns et al., 1990b).”

“…10: (Knafo et al., 2009), 11: (Lalonde et al., 2005), 12: (O’leary and Brown, 2009), 13: (Holcomb et al., 1999), 14: (Dineley et al., 2002), 15: (Trinchese et al., 2004), 16: (Arendash et al., 2001a), 17: (Arendash et al., 2001b), 18: (Tohda et al., 2012), 19: (Morgan et al., 2000), 20:…”

“…studies have linked depression and AD (Chen et al., 1999; Charlson and Peterson, 2002; Ownby et al., 2006; Lenoir et al., 2011; Diniz et al., 2013), and several even consider late-life depression a significant risk factor for future development of AD (Butters et al., 2000, 2008; Diniz et al., 2013).”

“…2013), 27: (Devi and Ohno, 2010), 28:(Devi and Ohno, 2012), 29: (Urano and Tohda, 2010), 30: (Oddo et al., 2003), 31: (Clinton et al., 2007), 32: (Carroll et al., 2007), 33: (Gimenez-Llort et al., 2007), 34: (Billings et al., 2005), 35: (Nelson et al., 2007b), 36: (Pietropaolo et al., 2008),…”

“…exhibit increased locomotor activity (Dodart et al., 1999; King et al., 1999; Arendash et al., 2001b; Dumont et al., 2004; Hyde et al., 2005; Cheng et al., 2007; Gil-Bea et al., 2007; Pietropaolo et al., 2008; Sanchez-Mejia et al., 2008; Ambree et al., 2009; Cisse et al., 2011; Mori et al., 2013).”

“Second, it appears that density of neuritic plaques correlates more strongly with the cognitive deficits than do “diffuse” amyloid plaques (Mckee et al., 1991; Crystal et al., 1993; Tiraboschi et al., 2004; Nelson et al., 2007a; Braak et al., 2011).”

“However, these cognitive deficits are not robust at this age, as others have observed no such deficit (Holcomb et al., 1999; Arendash et al., 2001a).”

“In both the Wisconsin Card Sorting Task in humans and set-shifting tasks in mice, the dorsolateral and orbital prefrontal cortex is critical for successful performance (Weinberger et al., 1986; Berman et al., 1995; Brigman et al., 2005; Bissonette et al., 2008).”

“…et al., 2002), 6: (Chen et al., 2000), 7: (Hsiao et al., 1996), 8: (Dineley et al., 2002), 9: (Chapman et al., 1999), 10: (King et al., 1999), 11: (Arendash et al., 2001a), 12: (Arendash et al., 2004), 13: (Ohno et al., 2004), 14: (Yassine et al., 2013), 15: (Westerman et al., 2002), 16:…”

“Consistent with this progression of pathology, the earliest detectable deficits in cognition are seen in medial temporal lobe-dependent episodic memory (Bondi et al., 1999; Collie and Maruff, 2000; Schmitt et al., 2000; Smith et al., 2007).”

“No deficits were seen in alternation tasks of working memory for this model (Lalonde et al., 2004; Cao et al., 2007).”

“Numerous meta-analysis studies have linked depression and AD (Chen et al., 1999; Charlson and Peterson, 2002; Ownby et al., 2006; Lenoir et al., 2011; Diniz et al., 2013), and several even consider late-life depression a significant risk factor for future development of AD (Butters et al., 2000,…”

“Impairments in reference memory develop by 6 months and persist through the rest of the life of this model (Reiserer et al., 2007; Bernardo et al., 2009; O’leary and Brown, 2009).”

“…as well as dysfunction in language, praxis, and executive functioning (Flicker et al., 1984; Baddeley et al., 1986, 1991, 2001; Huff et al., 1987; Knopman and Ryberg, 1989; Hodges et al., 1992; Parasuraman and Nestor, 1993; Hodges and Patterson, 1995; Perry and Hodges, 1999; Salmon et al., 1999;…”

“However, animals with prefrontal cortex lesions display profound deficits in reversal learning (Chudasama, 2011; Izquierdo and Jentsch, 2012).”

“…flexibility Birrell and Brown, 2000 Reversal learning Adjustment to changes in reward contingency Executive function and working memory Butter, 1969; Bussey et al., 1997 What-Where-Which Task (WWWhich) The animal must associate an object (What) with its location (Where) in a specific visuospatial…”

“While less complex than attentional set shifting, reversal learning does require both cognitive flexibility and impulse control, thus tapping into components of human executive function (Chudasama, 2011; Stopford et al., 2012).”

“…1990, 1997, 1998; Mckee et al., 1991; Arriagada et al., 1992; Bierer et al., 1995; Davis et al., 1995; Dickson et al., 1995; Nagy et al., 1995, 1999; Cummings et al., 1996; Berg et al., 1998; Grober et al., 1999; Sabbagh et al., 1999; Gold et al., 2000; Mungas et al., 2001; Riley et al., 2002;…”

“…(Lassalle et al., 2008), 19: (Morgan et al., 2000), 20: (Sturchler-Pierrat et al., 1997), 21: (Van Dam et al., 2003), 22: (Huang et al., 2006), 23: (Heneka et al., 2006), 24: (Prut et al., 2007), 25: (Kelly et al., 2003), 26: (Lalonde et al., 2002), 27: (Dumont et al., 2004), 28: (Chishti et al.,…”

“These aggressive disruptions appear to develop later than the onset of cognitive deficits in this model (Kelly et al., 2003; Van Dam et al., 2003; Vloeberghs et al., 2006).”

“Touchscreen versions of this task are also available in which the nose poke holes and stimulus lights are replaced with an LCD screen (Romberg et al., 2011; Bussey et al., 2012).”

“…seen clinically and those seen in the AD mouse models are: (1) as the severity of the disease progresses, the worse the sleep disturbances become (Smith, 1985; Graves et al., 2001; Huitron-Resendiz et al., 2002, 2005) and (2) the greater the sleep disruptions are, the more severe the cognitive…”

“This model develops cognitive deficits by 3 months of age in spatial working memory (Ohno et al., 2006; Urano and Tohda, 2010).”

“The MMSE has excellent reproducibility that lends itself well to longitudinal use in tracking the progression of the cognitive impairments associated with AD (Jacqmin-Gadda et al., 1997; Aevarsson and Skoog, 2000; Chatfield et al., 2007).”

“Second, it appears that density of neuritic plaques correlates more strongly with the cognitive deficits than do “diffuse” amyloid plaques (Mckee et al., 1991; Crystal et al., 1993; Tiraboschi et al., 2004; Nelson et al., 2007a; Braak et al., 2011).”

“…from as low as 2% to as high as 85% (variability likely due to methods of assessment, diagnostic criteria, stage of AD participants, and other factors) (Mendez et al., 1990; Burns et al., 1990a; Migliorelli et al., 1995a,b; Devanand et al., 1996; Cummings, 2000; Apostolova and Cummings, 2008).”

“Slight deficits in executive functioning are first detectable near the end of the preclinical phase of AD but after the observed deficits in episodic and semantic memory (Storandt et al., 2006; Twamley et al., 2006).”

“…on episodic-like memory across a number of animal species has suggested otherwise, and several mouse behavioral tasks designed at assessing episodic-like memory have been developed (Clayton and Dickinson, 1998; Clayton et al., 2001; Griffiths and Clayton, 2001; Morris, 2001; Davis et al., 2013a,b).”

“…well documented connection between depression and AD and having a wide range of potentially applicable tools to study depression in animal models (Seligman et al., 1975; Jolly et al., 1999; Song and Leonard, 2005; Flint and Shifman, 2008; Nestler and Hyman, 2010), very little work has been…”

“…et al., 2000; Mungas et al., 2001; Riley et al., 2002; Silver et al., 2002; Tiraboschi et al., 2002; Guillozet et al., 2003; Bennett et al., 2004; Kraybill et al., 2005; Holtzer et al., 2006; Markesbery et al., 2006; Koepsell et al., 2008; Whitwell et al., 2008; Beach et al., 2009; Brayne et…”

“Slight deficits in executive functioning are first detectable near the end of the preclinical phase of AD but after the observed deficits in episodic and semantic memory (Storandt et al., 2006; Twamley et al., 2006).”

“…1970; Duyckaerts et al., 1990, 1997, 1998; Mckee et al., 1991; Arriagada et al., 1992; Bierer et al., 1995; Davis et al., 1995; Dickson et al., 1995; Nagy et al., 1995, 1999; Cummings et al., 1996; Berg et al., 1998; Grober et al., 1999; Sabbagh et al., 1999; Gold et al., 2000; Mungas et al.,…”

“In many ways, set-shifting tasks are similar to the Wisconsin Card Sorting Task in that they form the gold standard for assessing executive function (Drewe, 1974; Robinson et al., 1980; Arnett et al., 1994).”

“Increased aggressive behaviors are another common behavioral symptom of AD and present themselves in as much as 65% of AD patients (Burns et al., 1990b).”

“…have been well characterized across the lifespan of this mouse model in water based spatial working memory tasks (Lalonde et al., 2005; Park et al., 2006; Cao et al., 2007; Sood et al., 2007; Ding et al., 2008; Volianskis et al., 2010; Zhang et al., 2011; Cramer et al., 2012; Ma et al., 2012).”

“In the following section, we will cover several of the most common neuropsychological tests used clinically to assess the mental status and memory disruptions in AD (for more in depth reviews see Perry and Hodges, 1999; Budson and Price, 2005; Bondi et al., 2008; Weintraub et al., 2012).”

“…used as clinical diagnostic tools (Schmitt, 1994) as well as to track the progression of the disease (Flicker et al., 1984; Morris et al., 1989; Storandt and Hill, 1989; Storandt, 1991; Welsh et al., 1991, 1992; Locascio et al., 1995; Albert, 1996; Storandt et al., 1998; Schmitt et al., 2000;…”

“Other common tasks of murine spatial working memory are the Radial Arm Water Maze (RAWM) and the Barnes Maze (Barnes, 1979; Diamond et al., 1999; Alamed et al., 2006).”

“…tools (Schmitt, 1994) as well as to track the progression of the disease (Flicker et al., 1984; Morris et al., 1989; Storandt and Hill, 1989; Storandt, 1991; Welsh et al., 1991, 1992; Locascio et al., 1995; Albert, 1996; Storandt et al., 1998; Schmitt et al., 2000; Salmon and Bondi, 2009).”

“As with other non-cognitive behavioral symptoms of AD, increased aggression can be emotionally stressful to both the patient and caregivers (Murman et al., 2002a,b).”

“However, methodology used to assess spatial memory appears to be very important, as several different reports have failed to observe these same deficits at various ages (Hsiao et al., 1996; Arendash et al., 2001a; King and Arendash, 2002).”

“Deficits in recognition memory do not appear until much later, first appearing at 12 months of age in the NOR task (Oules et al., 2012; Yassine et al., 2013).”

“…(Dodart et al., 1999; Janus and Westaway, 2001; Auld et al., 2002; Dumont et al., 2004; Hyde et al., 2005; Cheng et al., 2007; Gil-Bea et al., 2007; Gimenez-Llort et al., 2007; Pietropaolo et al., 2008; Cisse et al., 2011) and have been linked to altered APP metabolism, amyloid levels, and disease…”

“Not all AD cases fall within the standard NFT distribution described by the Braak staging (Hof et al., 1997; Abner et al., 2011; Murray et al., 2011).”

“…the majority of models do display these disturbances and the pre-vailing thought is that this behavioral phenotype of disinhibition may be akin to the disinhibition seen in AD patients (exemplified by unacceptable behavior and inappropriate euphoria) (Daffner et al., 1992; Chung and Cummings, 2000).”

“Thus, great efforts have been made to better understand the profile of cognitive deficits associated with early AD, and have resulted in earlier and more reliable clinical diagnosis (Bondi et al., 1995, 1999; Jacobson et al., 2002; Lange et al., 2002; Mickes et al., 2007).”

“…et al., 1992; Bierer et al., 1995; Davis et al., 1995; Dickson et al., 1995; Nagy et al., 1995, 1999; Cummings et al., 1996; Berg et al., 1998; Grober et al., 1999; Sabbagh et al., 1999; Gold et al., 2000; Mungas et al., 2001; Riley et al., 2002; Silver et al., 2002; Tiraboschi et al., 2002;…”

“Consistent with this progression of pathology, the earliest detectable deficits in cognition are seen in medial temporal lobe-dependent episodic memory (Bondi et al., 1999; Collie and Maruff, 2000; Schmitt et al., 2000; Smith et al., 2007).”

“There have been numerous clinicopathological studies attempting to correlate amyloid plaques with the cognitive deficits seen in AD (Blessed et al., 1968; Tomlinson et al., 1970; Duyckaerts et al., 1990, 1998; Berg et al., 1998; Gold et al., 2000; Mungas et al., 2001; Tiraboschi et al., 2002, 2004; Guillozet et al., 20…”

“…on episodic-like memory across a number of animal species has suggested otherwise, and several mouse behavioral tasks designed at assessing episodic-like memory have been developed (Clayton and Dickinson, 1998; Clayton et al., 2001; Griffiths and Clayton, 2001; Morris, 2001; Davis et al., 2013a,b).”

“…aggression, stereotypic behavior, circadian rhythm disturbances, and anxiety (Ancoli-Israel et al., 1989; Okawa et al., 1991; Vitiello et al., 1992; Bliwise, 1994; Satlin et al., 1995; Van Someren et al., 1996; Hope et al., 1998; Harper et al., 2004; Shin et al., 2005; Tan et al., 2005).”

“Non-cognitive symptoms associated with AD shown in the mouse include increased locomotor activity (Dodart et al., 1999; King et al., 1999; Arendash et al., 2001b; Dumont et al., 2004; Hyde et al., 2005; Cheng et al., 2007; Gil-Bea et al., 2007; Pietropaolo et al., 2008; Sanchez-Mejia et al., 2008;…”

“…tools (Schmitt, 1994) as well as to track the progression of the disease (Flicker et al., 1984; Morris et al., 1989; Storandt and Hill, 1989; Storandt, 1991; Welsh et al., 1991, 1992; Locascio et al., 1995; Albert, 1996; Storandt et al., 1998; Schmitt et al., 2000; Salmon and Bondi, 2009).”

“…(Flicker et al., 1984; Baddeley et al., 1986, 1991, 2001; Huff et al., 1987; Knopman and Ryberg, 1989; Hodges et al., 1992; Parasuraman and Nestor, 1993; Hodges and Patterson, 1995; Perry and Hodges, 1999; Salmon et al., 1999; Perry et al., 2000; Backman et al., 2001; Lambon Ralph et al., 2003).”

“…et al., 2002; Vloeberghs et al., 2004; Wisor et al., 2005; Ambree et al., 2006; Sterniczuk et al., 2010; Bedrosian et al., 2011), and increased aggression (Moechars et al., 1996, 1998; Van Dorpe et al., 2000; Ambree et al., 2006; Vloeberghs et al., 2006; Pugh et al., 2007; Alexander et al., 2011).”

“For a disease process that is known to occur over a decade or more (Blennow and Zetterberg, 2013; Rosen and Zetterberg, 2013; Rosen et al., 2013), and encompasses the age range where people are likely to die of other causes, it is inevitable that many people will die in a prodromal or “preclinical”…”

“These early deficits in episodic memory are followed closely by deficits in semantic memory, and both are developed before other deficits in cognitive domains such as attention, visuospatial memory, or executive function (Bondi et al., 2008).”

“While this behavior is in itself a non-cognitive behavior, it has been reported to possibly have important effects on patient cognition (Smith, 1985; Graves et al., 2001).”

“The rodent 5-CSRTT is analogous to Leonard’s 5-CSRTT used in humans (Wilkinson, 1963).”

“…et al., 2004), 3: (Dodart et al., 1999), 4: (Hartman et al., 2005), 5: (Dodart et al., 2002), 6: (Chen et al., 2000), 7: (Hsiao et al., 1996), 8: (Dineley et al., 2002), 9: (Chapman et al., 1999), 10: (King et al., 1999), 11: (Arendash et al., 2001a), 12: (Arendash et al., 2004), 13: (Ohno et…”

“…(approximately 3 months of age), and the PS1 [Tg2576 + PS1 (M146L)], 3 × TgAD, and APP23 mice developing last (approximately 6–9 months of age) (Dodart et al., 1999; King et al., 1999; Arendash et al., 2001b; Dumont et al., 2004; Hyde et al., 2005; Cheng et al., 2007; Gil-Bea et al., 2007;…”

“Similar to the reported activity disturbances, circadian rhythm disruptions are also observed in many of the AD mouse models (Huitron-Resendiz et al., 2002; Vloeberghs et al., 2004; Wisor et al., 2005; Ambree et al., 2006; Sterniczuk et al., 2010; Bedrosian et al., 2011).”

“For example, there exist versions of both the RAM and RAWM that are considered non-spatial working memory tasks (Olton and Feustle, 1981; Crusio et al., 1993; Hyde et al., 2000).”

“By 15 months of age the spatial working memory is consistently impaired throughout the rest of the life span (Morgan et al., 2000; Arendash et al., 2001b; Gordon et al., 2001; Sadowski et al., 2004; Wilcock et al., 2004).”

“Anxiety disturbances have been reported in many of the AD mouse models (Moechars et al., 1996, 1999; Lalonde et al., 2003, 2004; Gil-Bea et al., 2007; Reiserer et al., 2007; Lassalle et al., 2008; Espana et al., 2010; Bedrosian et al., 2011; Cisse et al., 2011; Murakami et al., 2011; Filali et al.,…”

“These aggressive disruptions appear to develop later than the onset of cognitive deficits in this model (Kelly et al., 2003; Van Dam et al., 2003; Vloeberghs et al., 2006).”

“Similarly, the SBT was the first mental status examination to be correlated with amyloid plaque burden at autopsy (Carpenter et al., 2011).”

“…exhibit increased locomotor activity (Dodart et al., 1999; King et al., 1999; Arendash et al., 2001b; Dumont et al., 2004; Hyde et al., 2005; Cheng et al., 2007; Gil-Bea et al., 2007; Pietropaolo et al., 2008; Sanchez-Mejia et al., 2008; Ambree et al., 2009; Cisse et al., 2011; Mori et al., 2013).”

“…et al., 2013), anxiety (Moechars et al., 1996, 1999; Lalonde et al., 2003, 2004; Gil-Bea et al., 2007; Reiserer et al., 2007; Lassalle et al., 2008; Espana et al., 2010; Bedrosian et al., 2011; Cisse et al., 2011; Murakami et al., 2011; Filali et al., 2012), circadian disturbances…”

“…et al., 2002; Guillozet et al., 2003; Bennett et al., 2004; Kraybill et al., 2005; Holtzer et al., 2006; Markesbery et al., 2006; Koepsell et al., 2008; Whitwell et al., 2008; Beach et al., 2009; Brayne et al., 2009; Giannakopoulos et al., 2009; Sabbagh et al., 2010; Robinson et al., 2011).”

“It has become increasingly clear that identifying and targeting the cognitive deficits that occur early in the course of the disease is critical to producing the maximum impact of treatment on cognitive function and quality of life (Salmon et al., 2002).”

“However, the homology between mouse and human versions of these tasks is far from perfect, and caution should be used when drawing conclusions from the rodent 5-CSRTT and applying them to human attention (Young et al., 2009).”

“These disturbances are characterized by the AD patient’s propensity to frequently awaken during the nighttime and to increase the amount of time slept during the day (Ancoli-Israel et al., 1989; Okawa et al., 1991).”

“…(Oules et al., 2012), 18: (Lassalle et al., 2008), 19: (Morgan et al., 2000), 20: (Sturchler-Pierrat et al., 1997), 21: (Van Dam et al., 2003), 22: (Huang et al., 2006), 23: (Heneka et al., 2006), 24: (Prut et al., 2007), 25: (Kelly et al., 2003), 26: (Lalonde et al., 2002), 27: (Dumont et al.,…”

“These impairments are generally followed temporally by impairments in associative learning and reference memory, as assessed by maze alternation (Lalonde et al., 2012) and fear conditioning tasks (Kobayashi and Chen, 2005).”

“Cognitive decline is a defining feature of AD, and many mouse models have been developed that recapitulate aspects of the cognitive impairments seen in AD (Elder et al., 2010; Hochgrafe et al., 2013; Platt et al., 2013).”

“Response inhibition is required for the appropriate control of an individual’s behavioral actions in response to a stimulus (Robbins, 1996; Humby et al., 1999; Perry and Hodges, 1999; Romberg et al., 2013a).”

“…have been well characterized across the lifespan of this mouse model in water based spatial working memory tasks (Lalonde et al., 2005; Park et al., 2006; Cao et al., 2007; Sood et al., 2007; Ding et al., 2008; Volianskis et al., 2010; Zhang et al., 2011; Cramer et al., 2012; Ma et al., 2012).”

“…al., 2007), 33: (Gimenez-Llort et al., 2007), 34: (Billings et al., 2005), 35: (Nelson et al., 2007b), 36: (Pietropaolo et al., 2008), 37: (Filali et al., 2012), 38: (Arsenault et al., 2011), 39: (Stewart et al., 2011), 40: (Halagappa et al., 2007). working memory tasks starting at 3 months of age.”

“…seen in AD (Blessed et al., 1968; Tomlinson et al., 1970; Duyckaerts et al., 1990, 1998; Berg et al., 1998; Gold et al., 2000; Mungas et al., 2001; Tiraboschi et al., 2002, 2004; Guillozet et al., 2003; Kraybill et al., 2005; Holtzer et al., 2006; Markesbery et al., 2006; Nelson et al., 2007a,…”

“…the majority of models do display these disturbances and the pre-vailing thought is that this behavioral phenotype of disinhibition may be akin to the disinhibition seen in AD patients (exemplified by unacceptable behavior and inappropriate euphoria) (Daffner et al., 1992; Chung and Cummings, 2000).”

“Most studies of MCI patients show consistent impairments in verbal recall (Larrieu et al., 2002; Tuokko et al., 2005; Kryscio et al., 2006) and a decline in general memory functioning (Tuokko et al., 2005; Bondi et al., 2008).”

“Second, it appears that density of neuritic plaques correlates more strongly with the cognitive deficits than do “diffuse” amyloid plaques (Mckee et al., 1991; Crystal et al., 1993; Tiraboschi et al., 2004; Nelson et al., 2007a; Braak et al., 2011).”

“There have been many clinicopathological studies that have correlated amyloid plaques with cognitive deficits in AD, with an emerging picture that the strongest correlation exists in the earliest stages of the disease and this association greatly weakens as NFTs and neocortical degeneration become more widespread [9,…”

“Apart from potential overexpression artifacts, it has been difficult to standardize the phenotypes of the various models because of their construction with different promoters, transgene constructs, and mouse strains (Webster et al , 2014; Foley et al , 2015).”