Neurogenic abnormalities in Alzheimer's disease differ between stages of neurogenesis and are partly related to cholinergic pathology
Highlights
► Reduced neurogenic stem cells in Alzheimer's disease. (AD) ► Increased neurogenic proliferation in AD. ► Negative influence of cholinergic pathology on neurogenesis.
Introduction
Neurogenesis (NG) occurs throughout life in the brain of adult mammals in the subventricular zone (SVZ) of the lateral ventricles including a layer in the ventral temporal horn overlying the hippocampus (Bird et al., 1983, Curtis et al., 2007, Drapeau et al., 2003) and in the sub-granular layer (SGL) of the dentate gyrus (Eriksson et al., 1998). Neuroblasts from the SVZ constitute the rostral migratory stream (RMS) which terminates in the olfactory bulb where those neuroblasts mature into GABA-ergic interneurons (Bedard and Parent, 2004, Birks et al., 2009) while neurons born in the adult SGL migrate into the granule cell layer (GL) of the dentate gyrus and mature into dentate granule cells (Crespel et al., 2005).
The process of NG is thought to take place in 5 stages (von Bohlen Und Halbach, 2007) and in hippocampal NG proliferative precursor cell stages, characterized by the presence of type-1, type-2, and type-3 cells, as well as postmitotic stages can be distinguished (Kempermann et al., 2004, Kempermann, 2011). Briefly, stage 1 (proliferation phase) is characterized by stem cells or progenitor cells that are positive for glial fibrillary acidic protein (GFAP) and nestin (Fukuda et al., 2003), the latter being a key marker of undifferentiated neuronal progenitor cells (Bernier et al., 2000). In addition Musashi-1 (Msi-1), an RNA binding protein involved in the Notch pathway via repression of Notch inhibiting m-Numb (Imai et al., 2001, Sakakibara et al., 1996), is expressed in neural progenitor cells including stem cells (Maslov et al., 2004, Sakakibara et al., 1996). The immunoreactive pattern of stage 1 corresponds to type-1 cells of hippocampal NG. However, type-1 cells represent stem cells and only 5% of cell divisions among nestin-expressing cells of the SGL are in type-1 cells (Kronenberg et al., 2003). Hence, type-1 cells do not have a highly proliferative capacity. In early stage 2 (differentiation phase) cells express nestin while at later time-points of stage 2 cells cease expressing nestin and start expressing doublecortin and polysialynated embryonic neural cell adhesion molecule (PSA-NCAM) (Fukuda et al., 2003, Kronenberg et al., 2003); PSA-NCAM is a cell surface glycoprotein involved in neural migration, neurite growth, and axonal branching during development and adulthood (Seki and Arai, 1993). In the hippocampus, stage 2 is thereby characterized by type-2 cells that are termed transiently amplifying progenitor cells (Kempermann, 2011) and are subdivided into type-2a and type-2b cells; both subtypes express nestin while only type-2b cells express doublecortin and PSA-NCAM. Type-2 cells are highly proliferative with type-2b cells being neuronally determined (Kempermann et al., 2004). In stage 3 (migration phase) type-3 cells, that are neuroblasts exhibiting first dendrites, express doublecortin, PSA-NCAM (Kempermann, 2011), and β-III-tubulin (Seri et al., 2004). These markers are also expressed in stage 4 (axonal and dendritic targeting) together with calretinin and neuron-specific nuclear protein (NeuN) (Brandt et al., 2003, Kempermann et al., 2004, Llorens-Martin et al., 2006, Ming and Song, 2005). In stage 5 (synaptic integration) neurons are positive for NeuN and Calbindin (Brandt et al., 2003, Kempermann et al., 2004). Stages 4 and 5 are postmitotic stages (Kempermann et al., 2004).
NG represents a key factor in plasticity of adult brain in response to environmental stimuli (Ge et al., 2006) and abnormalities in NG have been detected in neurodegenerative diseases such as Alzheimer's disease (AD) (Winner et al., 2011). Using doublecortin and PSA-NCAM staining Jin et al. (2004) demonstrated a significant increase in SGL neurogenesis in post-mortem brains of AD patients. On the other hand, a decline in the extent of proliferation of progenitor cells and their numbers has been suggested in AD (Brinton and Wang, 2006) and reductions in the proliferative marker Msi-1 in the SGL has been observed in both AD (Ziabreva et al., 2006) and dementia with Lewy bodies (Johnson et al., 2011). It was suggested recently that synaptic pathology and defective NG are related to progressive accumulation of amyloid-β protein (Aβ) oligomers in AD; Aβ may activate cyclin-dependent kinase 5 (CDK5), which plays a role in synaptic function and neuronal integrity, thereby impairing neuronal maturation in NG (Crews and Masliah, 2010). Similarly, NG might be impaired by the intracellular domain (AICD) of the amyloid precursor protein (APP) that is generated by the γ-secretase processing of APP (Ghosal et al., 2010).
Both the increase and decrease in NG have been described in transgenic mice that partly recapitulate AD pathology; long lasting impairment of NG is associated with amyloid deposition in a transgenic knock in a mouse model of familial AD (Zhang et al., 2007) while increased hippocampal NG was seen in the in APP/PS1 double transgenic mice (Yu et al., 2009). Reductions in NG and high levels of hyperphosphorylated tau in NG areas have been demonstrated in transgenic mice harboring familial AD-linked mutant APPswe/PS1DeltaE9 (Demars et al., 2010). Using the triple transgenic (3xTG) AD mouse model that generates both Aβ and tau pathology Hamilton et al. (2010) found in NG areas decreased numbers of proliferating cells, early lineage neural progenitors and neuroblasts at middle (11 months old) and old age (18 months old). These findings indicate that AD-associated mutations suppress NG early during disease development (Hamilton et al., 2010).
Cholinergic activity is assumed to be involved in NG as it is likely to be functionally important in controlling the generation of neural stem cells in adult brains since cholinergic drugs influence proliferative activity in these regions (Cooper-Kuhn et al., 2004). In both AD and dementias related to α-synuclein pathology there is evidence of a relationship between reduced progenitor activity and cortical cholinergic loss (Cooper-Kuhn et al., 2004), consistent with experimental animal studies demonstrating that lesions in ascending cholinergic tracts significantly reduce NG (Contestabile and Ciani, 2008).
However, data on the relation between cholinergic pathology and NG in hippocampal NG areas in AD are lacking; we therefore aimed to systematically investigate different stages of NG and choline-acetyltransferase (ChAT) immunoreactivity in hippocampal NG areas of post-mortem brains from both non-demented individuals and AD patients.
Section snippets
Material and methods
Brain tissue from 20 AD patients (mean age, 81.2 ± 7.0 years; 13 female) and 21 age matched non-demented controls (mean age, 80.9 ± 8.5 years; 13 female) was obtained from the Newcastle Brain Tissue Resource (NBTR). Brains were donated between 1982 and 2004 and collected in accordance with the approval of the Joint Ethics Committee of Newcastle and North Tyneside Health Authority and following NBTR brain banking procedures. There was no significant difference in age, gender or post-mortem delays
Results
Msi-1 stained small, undifferentiated cells in SVZ, SGL, and GL, including neuronal processes (Figs. 1A, F, K, and P). In the total study group Msi-1 IOD was highest in SVZ followed by GL and SGL (Table 2). In both SGL and GL but not in SVZ Msi-1 IOD was significantly lower in AD compared to controls (Table 2) and negatively correlated with Braak stages (SGL, rho = − 0.413, P < 0.01; GL, rho = − 0.556, P < 0.01, Figs. 2A–C). In SGL and GL Msi-1 IOD was significantly lower in Braak stage VI compared to
Discussion
The results of our study indicate that changes in hippocampal NG in AD differ between NG phases, NG niche areas and AD stages; while progenitor/stem cell marker Msi-1 (type-1 cells; proliferation phase) decreases, nestin (type-2a and -2b cells; differentiation phase) and to a lesser degree PSA-NCAM (type-2b and -3 cells; differentiation/migration phase and axonal/dendritic targeting) increase with the progression of AD (increasing Braak stages). On the other hand, no significant differences
Acknowledgments
The authors are grateful to Dr. Alan Alpar and Prof. Tibor Harkany, Karolinska Institutet, for reading this manuscript and providing us with helpful comments. This study was supported by a pilot and an equipment grant from the Alzheimer Research Trust and the Newcastle NIHR Biomedical Research Centre In Ageing and Age Related Diseases. Tissue for this study was provided by the Newcastle Brain Tissue Resource, which is funded in part by a grant from the UK Medical Research Council (G0400074).
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