Leigh A. Holcomb

Centella asiatica extract selectively decreases amyloid β levels in hippocampus of Alzheimer's disease animal model.

PSAPP mice expressing the ‘Swedish’ amyloid precursor protein and the M146L presenilin 1 mutations are a well‐characterized model for spontaneous amyloid β plaque formation. Centella asiatica has a long history of use in India as a memory enhancing drug in Ayurvedic literature. The study investigated whether Centella asiatica extract (CaE) can alter the amyloid pathology in PSAPP mice by administering CaE (2.5 or 5.0 g/kg/day) starting at 2 months of age prior to the onset of detectable amyloid deposition and continued for either 2 months or 8 months. A significant decrease in amyloid β 1–40 and 1–42 was detectable by ELISA following an 8 month treatment with 2.5 mg/kg of CaE. A reduction in Congo Red stained fibrillar amyloid plaques was detected with the 5.0 mg/kg CaE dose and long‐term treatment regimen. It was also confirmed that CaE functions as an antioxidant in vitro, scavenging free radicals, reducing lipid peroxidation and protecting against DNA damage. The data indicate that CaE can impact the amyloid cascade altering amyloid β pathology in the brains of PSAPP mice and modulating components of the oxidative stress response that has been implicated in the neurodegenerative changes that occur with Alzheimers disease. Copyright

5HTTLPR polymorphism and enlargement of the pulvinar : Unlocking the backdoor to the limbic system

BACKGROUND The 5HTTLPR genetic variant of the serotonin transporter (SERT), which consists of a long (SERT-l) and short (SERT-s) allele, has emerged as a major factor influencing emotional behavior and brain anatomy. The pulvinar nucleus of the thalamus projects to important limbic nuclei including the amygdala and cingulate cortex, is involved in the processing of stimuli with emotional content, and contains an abundance of SERT. METHODS Stereological methods were used to measure pulvinar neuron number in postmortem tissue from major depressive disorder (n = 11), bipolar disorder (n = 11), schizophrenia (n = 12), and control (n = 15) specimens from the Stanley Foundation Neuropathology Consortium. The effect of SERT genotype on pulvinar volume and neuron number was investigated by using analysis of covariance. RESULTS Analysis of covariance with diagnosis, SERT genotype, age, hemisphere, postmortem interval, and time-in-formalin covariates identified a 20% increase in pulvinar neuron number and volume in SERT-ss subjects. CONCLUSIONS The elevated number of pulvinar neurons in subjects with a SERT-ss genotype may serve to enhance subcortical input of emotionally relevant stimuli to the limbic system, providing a mechanism for the 5HTTLPR genetic variant to affect predisposition to conditions such as major depression.

Major depression, 5HTTLPR genotype, suicide and antidepressant influences on thalamic volume

BACKGROUND The 5HTTLPR genetic variant of the serotonin transporter gene (SERT or 5-HTT), which is comprised of a short (SERT-s) and a long (SERT-l) allele, is associated with major depressive disorder and post-traumatic brain disorder. AIMS The present study sought to determine whether the total thalamus and major subregions are altered in size in major depressive disorder and in relation to the 5HTTLPR genotype. METHOD We investigated the influence of 5HTTLPR genotype, psychiatric diagnosis, suicide and other clinical factors on the volume of the entire post-mortem thalamus. RESULTS Major depressive disorder, SERT-ss genotype and suicide emerged as independent factors contributing to an enlargement of the total thalamus. The majority of the volume enlargement associated with the SERT-ss genotype occurred in the pulvinar, whereas enlargement associated with major depressive disorder occurred in the limbic nuclei and in other regions of the thalamus. A history of antidepressant treatment was associated with reduced thalamic volume. CONCLUSIONS The 5HTTLPR genetic variation may affect behaviour and psychiatric conditions, in part, by altering the anatomy of the thalamus.

PSAPP mice exhibit regionally selective reductions in gliosis and plaque deposition in response to S100B ablation

BackgroundNumerous studies have reported that increased expression of S100B, an intracellular Ca2+ receptor protein and secreted neuropeptide, exacerbates Alzheimers disease (AD) pathology. However, the ability of S100B inhibitors to prevent/reverse AD histopathology remains controversial. This study examines the effect of S100B ablation on in vivo plaque load, gliosis and dystrophic neurons.MethodsBecause S100B-specific inhibitors are not available, genetic ablation was used to inhibit S100B function in the PSAPP AD mouse model. The PSAPP/S100B-/- line was generated by crossing PSAPP double transgenic males with S100B-/- females and maintained as PSAPP/S100B+/- crosses. Congo red staining was used to quantify plaque load, plaque number and plaque size in 6 month old PSAPP and PSAPP/S100B-/- littermates. The microglial marker Iba1 and astrocytic marker glial fibrillary acidic protein (GFAP) were used to quantify gliosis. Dystrophic neurons were detected with the phospho-tau antibody AT8. S100B immunohistochemistry was used to assess the spatial distribution of S100B in the PSAPP line.ResultsPSAPP/S100B-/- mice exhibited a regionally selective decrease in cortical but not hippocampal plaque load when compared to PSAPP littermates. This regionally selective reduction in plaque load was accompanied by decreases in plaque number, GFAP-positive astrocytes, Iba1-positive microglia and phospho-tau positive dystrophic neurons. These effects were not attributable to regional variability in the distribution of S100B. Hippocampal and cortical S100B immunoreactivity in PSAPP mice was associated with plaques and co-localized with astrocytes and microglia.ConclusionsCollectively, these data support S100B inhibition as a novel strategy for reducing cortical plaque load, gliosis and neuronal dysfunction in AD and suggest that both extracellular as well as intracellular S100B contribute to AD histopathology.

Lipid oxidation and modification of amyloid-β (Aβ) in vitro and in vivo.

Oxidative damage and amyloid-β (Aβ) protein misfolding are prominent features of Alzheimers disease (AD). In vitro studies indicated a direct linkage between these two features, where lipid oxidation products augmented Aβ misfolding. We tested this linkage further, mimicking specific conditions present in amyloid plaques. In vitro lipid oxidation and lipid modification of Aβ were thus performed with elevated levels of copper or physiological levels of calcium. These in vitro experiments were then confirmed by in vivo immunohistochemical and chemical tagging of oxidative damage in brains from the PSAPP mouse model of AD. Our in vitro findings indicate that: 1) high levels of copper prevent lipid oxidation; 2) physiological concentrations of calcium reduce 4 hydroxy-2-nonenal (HNE) modification of Aβ; and 3) anti-Aβ and HNE antibody epitopes are differentially masked. In vivo we demonstrated increased lipid oxidation around plaques but 4) a lack of immunological colocalization of HNE-adducts with Aβ. Thus, the lack of colocalization of Aβ and HNE-adduct immunostaining is most likely due to a combination of metals inhibiting HNE modification of Aβ, quenching lipid oxidation and a masking of HNE-Aβ histopathology. However, other forms of oxidative damage colocalize with Aβ in plaques, as demonstrated using a chemical method for identifying oxidative damage. Additionally, these findings suggest that HNE modification of Aβ may affect therapeutic antibodies targeting the amino terminal of Aβ and that metals effect on lipid oxidation and lipid modification of Aβ could raise concerns on emerging anti-AD treatments with metal chelators.