Downstream effects of polypathology on neurodegeneration of medial temporal lobe subregions.

The medial temporal lobe (MTL) is a nidus for neurodegenerative pathologies and therefore an important region in which to study polypathology. We investigated associations between neurodegenerative pathologies and the thickness of different MTL subregions measured using high-resolution post-mortem MRI. Tau, TAR DNA-binding protein 43 (TDP-43), amyloid-ß and α-synuclein pathology were rated on a scale of 0 (absent)-3 (severe) in the hippocampus and entorhinal cortex (ERC) of 58 individuals with and without neurodegenerative diseases (median age 75.0 years, 60.3% male). Thickness measurements in ERC, Brodmann Area (BA) 35 and 36, parahippocampal cortex, subiculum, cornu ammonis (CA)1 and the stratum radiatum lacunosum moleculare (SRLM) were derived from 0.2 × 0.2 × 0.2 mm3 post-mortem MRI scans of excised MTL specimens from the contralateral hemisphere using a semi-automated approach. Spearman's rank correlations were performed between neurodegenerative pathologies and thickness, correcting for age, sex and hemisphere, including all four proteinopathies in the model. We found significant associations of (1) TDP-43 with thickness in all subregions (r = - 0.27 to r = - 0.46), and (2) tau with BA35 (r = - 0.31) and SRLM thickness (r = - 0.33). In amyloid-ß and TDP-43 negative cases, we found strong significant associations of tau with ERC (r = - 0.40), BA35 (r = - 0.55), subiculum (r = - 0.42) and CA1 thickness (r = - 0.47). This unique dataset shows widespread MTL atrophy in relation to TDP-43 pathology and atrophy in regions affected early in Braak stageing and tau pathology. Moreover, the strong association of tau with thickness in early Braak regions in the absence of amyloid-ß suggests a role of Primary Age-Related Tauopathy in neurodegeneration.

Subicular and CA1 hippocampal projections to the accessory olfactory bulb.

The hippocampal formation is anatomically and functionally related to the olfactory structures especially in rodents. The entorhinal cortex (EC) receives afferent projections from the main olfactory bulb; this constitutes an olfactory pathway to the hippocampus. In addition to the olfactory system, most mammals possess an accessory olfactory (or vomeronasal) system. The relationships between the hippocampal formation and the vomeronasal system are virtually unexplored. Recently, a centrifugal projection from CA1 to the accessory olfactory bulb has been identified using anterograde tracers. In the study reported herein, experiments using anterograde tracers confirm this projection, and injections of retrograde tracers show the distribution and morphology of a population of CA1 and ventral subicular neurons projecting to the accessory olfactory bulb of rats. These results extend previous descriptions of hippocampal projections to the accessory olfactory bulb by including the ventral subiculum and characterizing the morphology, neurochemistry (double labeling with somatostatin), and distribution of such neurons. These data suggest feedback hippocampal control of chemosensory stimuli in the accessory olfactory bulb. Whether this projection processes spatial information on conspecifics or is involved in learning and memory processes associated with chemical stimuli remains to be elucidated.

Neurogenesis in subclasses of vomeronasal sensory neurons in adult mice.

The vomeronasal sensory epithelium contains two distinct populations of vomeronasal sensory neurons. Apical neurons express G(i) (2) (α) -linked V1R vomeronasal receptors and project to the anterior portion of the accessory olfactory bulb, while basal neurons express G(o) (α) -linked V2R receptors and project to the posterior portion. Sensory neurons expressing V1R and V2R vomeronasal receptors are sensitive to different stimuli. Neurons in the vomeronasal system undergo continuous cell turnover during adulthood. To analyze over time neurogenesis of the different sensory cell populations, adult mice were injected with bromodeoxyuridine (BrdU) and sacrificed at postinjection days 1, 3, 5, 7, and 11. Newborn vomeronasal neurons were revealed by antibodies against BrdU while subclasses of vomeronasal neurons were identified using antibodies against G(o) (α) or G(i) (2) (α) proteins. To ascertain whether G proteins are early expressed during neurogenesis, multiple labeling experiments using PSA-NCAM and doublecortin were performed. Distribution of BrdU-labeled cells was analyzed in angular segments from the margin of the sensory epithelium. No sexual differences were found. Within survival groups, BrdU-G(o) (α) labeled cells were found more marginally when compared with BrdU-G(i) (2) (α) labeled cells. The number of BrdU-positive cells decreased from day 1 to day 3 to remain constant afterwards. The relative proportions of BrdU-G(i) (2) (α) and BrdU-G(o) (α) labeled cells remained similar and constant from postinjection day 1 onwards. This rate was also comparable with BrdU-positive cells starting day 3. These results indicate an early, constant, and similar rate of neurogenesis in the two major subclasses of vomeronasal neurons, which suggests that both cell populations maturate independently.

Somatostatin, tau, and beta-amyloid within the anterior olfactory nucleus in Alzheimer disease.

Impaired olfaction is an early symptom of Alzheimer disease (AD). This likely to reflect neurodegenerative processes taking place in basal telencephalic structures that mediate olfactory processing, including the anterior olfactory nucleus. Betaeta-amyloid (Abeta) accumulation in AD brain may relate to decline in somatostatin levels: somatostatin induces the expression of the Abeta-degrading enzyme neprilysin and somatostatin deficiency in AD may therefore reduce Abeta clearance. We have investigated the expression of somatostatin in the anterior olfactory nucleus of AD and control brain. We report that somatostatin levels were reduced by approximately 50% in AD brain. Furthermore, triple-immunofluorescence revealed co-localization of somatostatin expression with Abeta (65.43%) with Abeta and tau (19.75%) and with tau (2.47%). These data indicate that somatostatin decreases in AD and its expression may be linked with Abeta deposition.

Fate of marginal neuroblasts in the vomeronasal epithelium of adult mice.

Chemical stimuli are sensed through the olfactory and vomeronasal epithelia, and the sensory cells of both systems undergo neuronal turnover during adulthood. In the vomeronasal epithelium, stem cells adjacent to the basal lamina divide and migrate to replace two classes of sensory neurons: apical neurons that express G(i2alpha)-linked V1R vomeronasal receptors and project to the anterior accessory olfactory bulb, and basal neurons that express G(oalpha)-linked V2R receptors and project to the posterior accessory olfactory bulb. Most of the dividing cells are present in the margins of the epithelium and only migrate locally. Previous studies have suggested that these marginal cells may participate in growth, sensory cell replacement or become apoptotic before maturation; however, the exact fate of these cells have remained unclear. In this work we investigated the fate of these marginal cells by analyzing markers of neurogenesis (bromodeoxyuridine incorporation), apoptosis (caspase-3), and neuronal maturation (olfactory marker protein and Neurotrace Nissl stain). Our data reveal a pool of dividing cells in the epithelial margins that predominantly give rise to mature neurons and only rarely undergo apoptosis. Newly generated cells are several times more numerous than apoptotic cells. These marginal neuroblasts could therefore constitute a net neural addition zone during adulthood.