Neurogenic abnormalities in Alzheimer's disease differ between stages of neurogenesis and are partly related to cholinergic pathology

Neurogenesis occurs in the subventricular zone and the sub-granular layer of the hippocampus and is thought to take place in 5 stages, including proliferation, differentiation, migration, targeting, and integration phases, respectively. In Alzheimer’s disease (AD) both increased and decreased neurogenesis has been reported and cholinergic activity is assumed to be involved in neurogenesis. The aim of this study was to systematically assess different phases of neurogenesis and their relation to AD and cholinergic pathology. We investigated post-mortem brain tissue from 20 AD patients and 21 non-demented controls that was neuropathologically characterized according to standardized criteria. Hippocampal sections were stained with antibodies against neurogenic markers Musashi-1, nestin, PSA-NCAM, doublecortin, and β-III-tubulin as well as ChAT (choline-acetyltransferase). Using image analysis immunoreactivity was assessed in the subventricular zone, the sub-granular layer, and the granule cell layer by determining the integrated optical density. In the sub-granular layer and the granule cell layer Musashi-1 and ChAT immunoreactivities were significantly lower in AD and decreased with increasing Braak stages. Conversely, immunorreactivities of both nestin and PSA-NCAM were significantly higher in AD and increased with increasing Braak stages while no changes were seen for doublecortin and β-III-tubulin, except for significantly higher doublecortin levels in the granule cell layer of AD cases. Of note, Musashi-1 immunoreactivity significantly correlated with ChAT immuonoreactivity across different Braak stages. In the subventricular zone only nestin immunoreactivity was significantly higher in AD and significantly increased with increasing Braak stages, while no significant differences were seen for all other markers. Our finding of a reduction of ChAT and Musashi-1 levels in AD is compatible with the assumption that cholinergic pathology per se has a detrimental influence on neurogenesis. We conclude that neurogenic abnormalities in AD differ between phases and areas of neurogenesis and stages of AD; while hippocampal stem cells (Musashi-1) decrease, proliferation (nestin) increases and differentiation/migration phase as well as axonal/dendritic targeting (doublecortin and β-III-tubulin) remains virtually unchanged. This suggests an attenuation of stem cells together with compensatory increased proliferation that, however, does not result in an increased number of migratory neuroblasts and differentiated neurons in AD

Dissociation between iron accumulation and ferritin upregulation in the aged substantia nigra:Attenuation by dietary restriction

Despite regulation, brain iron increases with aging and may enhance aging processes including neuroinflammation. Increases in magnetic resonance imaging transverse relaxation rates, R2 and R2*, in the brain have been observed during aging. We show R2 and R2* correlate well with iron content via direct correlation to semi-quantitative synchrotron-based X-ray fluorescence iron mapping, with age-associated R2 and R2* increases reflecting iron accumulation. Iron accumulation was concomitant with increased ferritin immunoreactivity in basal ganglia regions except in the substantia nigra (SN). The unexpected dissociation of iron accumulation from ferritin-upregulation in the SN suggests iron dyshomeostasis in the SN. Occurring alongside microgliosis and astrogliosis, iron dyshomeotasis may contribute to the particular vulnerability of the SN. Dietary restriction (DR) has long been touted to ameliorate brain aging and we show DR attenuated age-related in vivo R2 increases in the SN over ages 7 – 19 months, concomitant with normal iron-induction of ferritin expression and decreased microgliosis. Iron is known to induce microgliosis and conversely, microgliosis can induce iron accumulation, which of these may be the initial pathological aging event warrants further investigation. We suggest iron chelation therapies and anti-inflammatory treatments may be putative ‘anti-brain aging’ therapies and combining these strategies may be synergistic

Importance of Proactive Treatment of Depression in Lewy Body Dementias:The Impact on Hippocampal Neurogenesis and Cognition in a Post-Mortem Study

OBJECTIVE: To examine the impact of selective serotonin reuptake inhibitors (SSRIs) and depression on neurogenesis and cognition in dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD). // METHODS: Late-stage progenitor cells were quantified in the subgranular zone (SGZ) of the hippocampal dentate gyrus of DLB/PDD patients (n = 41) and controls without dementia (n = 15) and compared between treatment groups (unmedicated, SSRIs, acetyl cholinesterase inhibitors [AChEIs], combined SSRIs and AChEIs). // RESULTS: DLB/PDD patients had more doublecortin-positive cells in the SGZ compared to controls. The doublecortin-positive cell count was higher in the SGZ of patients treated with SSRIs and correlated to higher cognitive scores. // CONCLUSION: SSRI treatment was associated with increased hippocampal neurogenesis and preservation of cognition in DLB/PDD patients

Stage-Specific Changes in Neurogenic and Glial Markers in Alzheimer's Disease

Background: Reports of altered endogenous neurogenesis in people with Alzheimer's disease (AD) and transgenic AD models have suggested that endogenous neurogenesis may be an important treatment target, but there is considerable discrepancy among studies. We examined endogenous neurogenesis and glia changes across the range of pathologic severity of AD in people with and without dementia to address this key question. Methods: Endogenous neurogenesis and glia in the subventricular zone and dentate gyrus neurogenic niches were evaluated using single and double immunohistochemistry and a validated antibody selection for stage-specific and type-specific markers in autopsy tissue from a representative cohort of 28 participants in the Medical Research Council Cognitive Function and Ageing Study. Immunopositive cells were measured blinded to diagnosis using bright-field and fluorescent microscopy. Results: The number of newly generated neurons significantly declined only in the dentate gyrus of patients with severe tau pathology. No other changes in other neurogenic markers were observed in either of the neurogenic niches. Alterations in astrocytes and microglia were also observed in the dentate gyrus across the different stages of tau pathology. No change in any of the markers was observed in individuals who died with dementia compared with individuals who did not die with dementia. Conclusions: Alterations in endogenous neurogenesis appeared to be confined to a reduction in the generation of new neurons in the dentate gyrus of patients with AD and severe neurofibrillary tangle pathology and were accompanied by changes in the glia load. These data suggest that intervention enhancing endogenous neurogenesis may be a potential therapeutic target in AD. Crow

SOX2 and SOX3 Down-Regulation in LGE Neurons and SOX1/SOX2 Co-Expression in LGE Precursors

<p>Immunofluorescence of coronal sections at LGE levels in (A–C) E15- and (D–L) E13-stage wild-type embryos visualized on a confocal microscope: antibody staining for (A, D, G, and J) SOX1 (red), (B, E, H, and K) SOX2 (green), (C) SOX3 (green), (D–L) double SOX1 (red) and SOX2 (green), and (F, I, and L) merged. In the OT area and the LGE mantle, there are more neurons expressing SOX1 (A and J) than SOX2 (B and K) and SOX3 (C). Note the extensive co-expression of the SOX1 and SOX2 in precursors (D–I). (G–I) are higher magnifications of the areas within the rectangles. Scale bar = 300 μm.</p

Normal Precursor Proliferation and Neurogenesis but Loss of OT Neuronal Differentiation in the Absence of SOX1

<p>Coronal brain sections from the ventral telencephalon of wild-type (+/+) and <i>Sox1</i>-null (−/−) embryos. TuJ1 immunolabeling (A and B) at E13 shows no difference in early neuronal differentiation embryos; in situ hybridization at E16 for <i>Brn4</i> (C and D) and <i>Robo</i> (E and F) shows absence of differentiation in the mutant at the prospective OT area. Red arrow in wild-type brain sections indicates OT. Telencephalic sections of wild-type (G, I, and K) and <i>Sox1</i>-null mutant (H, J, and L) embryonic brains were harvested 1 h after BrdU injection at E13 (G and H), E14 (I and J), and E15 (K and L) to detect actively dividing cells of the VZ/SVZ. Positive cells were visualized with anti-BrdU immunofluorescence (G–J) or with DAB staining (K and L). (K and L) show dorsal LGE area at high magnification. No differences were detected in the proliferation precursors at all stages examined, and no ectopic proliferation was observed in the mutant brains<i>.</i> Measurements and statistical analysis of BrdU-positive cells were performed on the DAB-stained sections, showing no significant differences (see <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0030186#st001" target="_blank">Table S1</a>). Scale bar = 300 μm (A and B), 300 μm (C–F), 500 μm (G–J), 500 μm (K and L).</p