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A number of studies have reported that adult neurogenesis is affected by pathological situations including stroke (Greenberg 2007), seizure (Parent et al 1997), acute trauma (Gao et al 2009, Miles & Kernie 2008) and neurodegenerative disease (Jin et al 2004c, Winner et al 2011). Neurodegenerative diseases are a broad range of disorders that have the common features including the progressive structural and functional loss of

neurons and glial cells in the brain and spinal cord (Winner et al 2011). Chronic neurodegeneration may exert various effects on NSPC maintenance (Kandasamy et al 2010), proliferation (Hoglinger et al 2004, Jin et al 2004c), survival and functional integration (Winner et al 2011). Furthermore, altered or even impaired adult neurogenesis has been described in models of neurodegenerative diseases such as Alzheimer’s disease (AD) (Jin et al 2004c, Mirochnic et al 2009, Rodriguez et al 2008), Parkinson’s disease (PD) (Crews et al 2008, Nuber et al 2008, Winner et al 2004) and Huntington’s disease (HD) (Kandasamy et al 2010, Kohl et al 2007). However, whether deficits in neurogenesis contribute to neurodegenerative diseases still remains unknown, although impaired olfaction and hippocampus associated cognitive and emotional deficits are commonly identified in variety of many neurodegenerative diseases (Winner et al 2011).

1.8.1 Neurogenesis in Alzheimer’s disease

Adult neurogenesis was suggested to contribute to learning and memory (Deng et al 2010). The rate of neurogenesis decreases with age, and seems to be further affected by AD pathogenesis (Jin et al 2004c, Kuhn et al 1996). A number of studies have used AD transgenic model animals to investigate this effect (Jin et al 2004a, Perry et al 2012, Yu et al 2009), although the mechanism underlying the neurogenesis response to AD pathology is still unknown (Jin et al 2004a, Martinez-Canabal 2014, Perry et al 2012, Yu et al 2009). Altered adult neurogenesis has been reported in AD transgenic animal models in the neurogenic niches such as the V-SVZ and DG-SGZ depending on post-mortem analysis (Marlatt & Lucassen 2010). Post-mortem studies of neurogenesis found enhanced expression of immature neuronal markers in the brain of AD patients (Jin et al 2004c). Furthermore, increased neurogenesis has been

identified in several AD transgenic mouse models (Jin et al 2004a, Lopez-Toledano & Shelanski 2007, Yu et al 2009). Nonetheless, some other studies challenge these observations and suggest that there are no changes or even decreased NSPC proliferation, in patients with AD (Boekhoorn et al 2006, Donovan et al 2006, Moon et al 2014, Rodriguez et al 2008).

However, the conflicting results may be due to combination of factors. Adult neurogenesis may change in response to AD pathology (Perry et al 2012, Yu et al 2009) such as Aβ deposition and synaptic loss (Kanemoto et al 2014, Perry et al 2012). Therefore, the increased NSPC proliferation found in AD cases may be a compensatory response to the pathologic changes of AD. Different types of AD pathology such as cholinergic degeneration may have detrimental effects on adult neurogenesis (Perry et al 2012). In addition, NSPC proliferation was reported to increase prior to the appearance of Aβ pathology, although the viability of NSPCs declines over the time course of AD pathogenesis (Chishti et al 2001, Kanemoto et al 2014). Studies of neurogenesis in AD are dependent on the use of AD transgenic

mouse models involving knock-in of various FAD-related human APP mutations,

often in combination with PS (PS1 or PS2) or tau mutations (Chishti et al 2001, Citron et al 1998, Mullan et al 1992, Oddo et al 2003). Indeed, these APP variants, or different PS species or other critical molecules may account, at least to some degree, for the observed divergence in neurogenic fate in the different AD transgenic models from these studies (Lazarov & Marr 2010). In addition, different APP or PS mutations or other gene insertions may exert different effects on adult neurogenesis, which also may be a cause of the inconsistent results obtained among these AD animal studies.

1.8.1.1 Role of PS on adult neurogenesis

PS is the catalytic domain of the γ - secretase complex (De Strooper et al 1998),

which is needed for proteolysis of a number of transmembrane proteins including

Notch and β - catenin as well as APP (De Strooper 2003). PS mutants that are

especially common in PS1 contribute to Aβ pathology by increasing the production of Aβ cleaved at position 42 (De Strooper et al 1998). PSs play a role in neural development or adult neurogenesis (Chen et al 2008, Shen et al 1997, Wong et al 1997). However, the precise mechanism by which PSs influence development is still unknown (Lazarov & Marr 2010). However, PS1 null mice display severe abnormalities in somitogenesis as well as neurogenesis in the brain (Shen et al 1997, Wong et al 1997). PS1 null mice do not survive postnatally, which has complicated studies of PS1 function in postnatal development (Shen et al 1997, Wong et al 1997). For this reason, investigations into the role of PS in neurogenesis in vivo have been carried out in PS1 transgenic mice (Lazarov & Marr 2010) or mice with a conditional deletion of the PS1 gene (Chen et al 2008, Feng et al 2001). In contrast, PS2 null mice show no obvious deficit, although inactivation of both PS2 and PS1 is embryonic lethal, suggesting functional redundancy between PS1 and PS2 (Donoviel et al 1999).

PS1 is expressed in NSPCs from neurogenic regions in the adult brain (Wen et al 2002a) and wild-type PS1 overexpression has been found to increase neurogenesis (Wen et al 2002b). Mice carrying a partial deletion of PS1 show no obvious difference in NSPC proliferation, which may possibly be explained by the compensatory effect exerted by PS2 (Chen et al 2008, Donoviel et al 1999). Nevertheless, mice harbouring a conditional PS1 deletion, but a conventional PS2 deletion, exhibit both enhanced NSPC proliferation and neuronal differentiation

(Chen et al 2008). This increased NSPC proliferation and differentiation may be due to the pathological stimulation, such as cortical neuron loss in mice with partial deletion of PS1 and completely null of PS2 (Chen et al 2008).

Surprisingly, mice with a single mutation in PS1 have only a minor reduction in the number of neuroblasts. Nevertheless, a dramatic decline in neuroblast number was observed in APP/PS1 double knock-in mice bearing a FAD mutation (Zhang et al 2007a). Most murine studies link FAD-associated PS1 mutations with impaired neurogenesis. For example, a more recent study reported that endogenous expression of a FAD-linked PS1 variants may be sufficient to impair NSPC proliferation, differentiation and survival (Veeraraghavalu et al 2010, Veeraraghavalu et al 2013), and another study suggested that expression of several PS1 mutants in NSPCs derived from the V-SVZ leads to a deficit in self-renewal and premature differentiation towards a neuronal fate in vitro (Gadadhar et al 2011, Lee et al 1997, Thinakaran et al 1996). In addition, PS may act as regulators of adult neurogenesis possibly via Notch signaling (De Strooper et al 1999, Wong et al 1997), therefore the FAD-related PS1 variants may cause a loss of PS1 function in neurogenesis regulation (De Strooper 2007).

1.8.1.2 Role of tau in neurogenesis

The pathological tau isoforms found in AD also have been suggested to have an impact on neurogenesis (Pristera et al 2013) although comparatively fewer studies have focused on that idea. A transgenic mouse model conditionally expressing a fragment of hyper - phosphorylated tau had reduced NSPC proliferation and survival and increased cell death in the dentate gyrus of hippocampus (Pristera et al 2013).

However, another study using animals containing a human tau isoform exhibited increased neurogenesis and cell cycle events (Schindowski et al 2008). This opposite result may be due to different pathological forms of tau being employed in the studies, therefore the impact of tau in neurogenesis warrants further study.