Icahn School of Medicine at Mount Sinai

About: Icahn School of Medicine at Mount Sinai is a education organization based out in New York, New York, United States. It is known for research contribution in the topics: Population & Medicine. The organization has 37488 authors who have published 76057 publications receiving 3704104 citations. The organization is also known as: Mount Sinai School of Medicine.

Intraneuronal Aβ42 Accumulation in Human Brain

Abstract: Alzheimer's disease (AD) is characterized by the deposition of senile plaques (SPs) and neurofibrillary tangles (NFTs) in vulnerable brain regions. SPs are composed of aggregated β-amyloid (Aβ) 40/42(43) peptides. Evidence implicates a central role for Aβ in the pathophysiology of AD. Mutations in βAPP and presenilin 1 (PS1) lead to elevated secretion of Aβ, especially the more amyloidogenic Aβ42. Immunohistochemical studies have also emphasized the importance of Aβ42 in initiating plaque pathology. Cell biological studies have demonstrated that Aβ is generated intracellularly. Recently, endogenous Aβ42 staining was demonstrated within cultured neurons by confocal immunofluorescence microscopy and within neurons of PS1 mutant transgenic mice. A central question about the role of Aβ in disease concerns whether extracellular Aβ deposition or intracellular Aβ accumulation initiates the disease process. Here we report that human neurons in AD-vulnerable brain regions specifically accumulate γ-cleaved Aβ42 and suggest that this intraneuronal Aβ42 immunoreactivity appears to precede both NFT and Aβ plaque deposition. This study suggests that intracellular Aβ42 accumulation is an early event in neuronal dysfunction and that preventing intraneuronal Aβ42 aggregation may be an important therapeutic direction for the treatment of AD.

Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer's disease.

Abstract: Objective: To examine the relationship between stereologic estimates of AD-related pathology and severity of cognitive deficits in brain aging. Background: Previous studies reported substantial contributions of neurofibrillary tangles (NFT), amyloid deposits, and neuronal loss to the development of dementia. However, the prediction of cognitive status based on nonstereologic quantification of these measures has led to conflicting results. Such studies have measured densities, rather than absolute numbers, and most do not take into account the potential interaction between the above pathologic hallmarks in a global multivariate analysis. Methods: Clinicopathologic study in 22 elderly cases. Cognitive status assessed prospectively using the Mini-Mental State Examination (MMSE); stereologic assessment of NFT, unaffected neurons, and total amyloid volume in the CA1 field of the hippocampus, entorhinal cortex, and area 9. Statistical analysis was performed using both univariate and multivariate linear regression models. Results: High total NFT counts but not amyloid volume were strongly associated with a lower number of unaffected neurons in all areas studied. A high proportion of variability in MMSE scores was explained by NFT and neuronal counts in the CA1 field (83% and 85.4%), entorhinal cortex (87.8% and 83.7%), and area 9 (87% and 79%); amyloid volume in the entorhinal cortex, but not in the CA1 field and area 9, accounted for 58.5% of MMSE variability. Multivariate analyses showed that total NFT counts in the entorhinal cortex and area 9 as well as neuron numbers in the CA1 field were the best predictors of MMSE score. Conclusions: These new stereologic data indicate that neuronal pathology in hippocampal formation and frontal cortex closely reflects the progression of cognitive deficits in brain aging and AD. They also demonstrate that amyloid volume has no additional predictive value, in terms of clinicopathologic correlations, beyond its interaction with NFT.

Common genetic variants on 5p14.1 associate with autism spectrum disorders

Abstract: Several lines of evidence point to genetic involvement in autism spectrum disorders (ASDs), neurodevelopmental and neuropsychiatric disorders characterized by impaired verbal communication and social interaction. The clinical and genetic complexities of the condition make it difficult to identify susceptibility factors, but two related studies now present robust evidence for a genetic involvement. The first, a genome-wide association study, identifies six single-nucleotide polymorphisms strongly associated with autism. These variants lie between two genes encoding neuronal cell-adhesion molecules (cadherins 9 and 10), suggesting possible involvement in ASD pathogenesis. The second study used copy number variation screens to identify genetic variants in two major gene pathways in children with ASDs. The changes are in the ubiquitin pathway, which has previously been associated with neurological disease, and in genes for neuronal cell-adhesion molecules.

The oxidant stress hypothesis in Parkinson's disease: Evidence supporting it

Abstract: Oxidant stress, due to the formation of hydrogen peroxide and oxygen-derived free radicals, can cause cell damage due to chain reactions of membrane lipid peroxidation. Because the substantia nigra is rich in dopamine, which can undergo both enzymatic oxidation via monoamine oxidase and nonenzymatic autoxidation, hydrogen peroxide and oxyradicals (superoxide anion radical and hydroxyl radical) are generated in this midbrain nucleus. Although proof that oxidant stress actually causes the loss of monoaminergic neurons in patients with Parkinson's disease is lacking, there is a considerable body of evidence from studies in both animals and humans that support the concept. (1) Neurotoxins that selectively destroy the dopaminergic neurons in the nigra, such as 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), appear to act via oxidant stress. (2) The substantia nigra of patients with Parkinson's disease reveals evidence of oxidant stress by the findings of increased lipid peroxidation and decreased reduced glutathione. (3) Total iron is increased and ferritin is reduced in the substantia nigra pars compacta in patients with Parkinson's disease. This combination suggests that this transition metal is in a low molecular weight form, capable of catalyzing nonenzymatic oxidative reactions, especially the conversion of hydrogen peroxide to hydroxyl radical, which is the most reactive of the oxygen radicals. (4) Neuromelanin, a product of dopamine autoxidation, can serve as a reservoir for iron, promoting the generation of oxyradicals. (5) Antioxidant defense mechanisms appear to be reduced in the parkinsonian substantia nigra with the findings of decreased activities of glutathione peroxidase and catalase.(ABSTRACT TRUNCATED AT 250 WORDS)