The Fetal Basis of Amyloidogenesis: Exposure to Lead and Latent Overexpression of Amyloid Precursor Protein and β-Amyloid in the Aging Brain

Basha, Riyaz; Wei, Wei; Bakheet, Saleh A.; Benitez, Nathalie; Siddiqi, Hasan K.; Ge, Yuan‐Wen; Lahiri, Debomoy K.; Zawia, Nasser H.

doi:10.1523/jneurosci.4335-04.2005

Cited by 329 publications

(261 citation statements)

References 36 publications

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“…In the APP processing pathway, the relative expression of APP coupled with the expression and activity of the APP secretases will likely dictate the amount of Aβ generated. Similar to previous studies [1,24,26], we observe increased APP protein expression in early post-natal animals relative to adult animals. It has been suggested that increased APP levels in young animals is due to its potential role in the developing brain [18].…”

Section: Discussionsupporting

confidence: 91%

Spatial and temporal control of age-related APP processing in genomic-based β-secretase transgenic mice

Chiocco

Lamb

2007

Neurobiology of Aging

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Genetic mutations associated with Alzheimer's disease (AD) in the Amyloid Precursor Protein (APP) gene specifically alter the production of the APP processing product, amyloid-β (Aβ) peptide, generated by β-and γ-secretases. The accumulation and deposition of Aβ is hypothesized to cause AD pathogenesis, leading to the debilitating neurological deficits observed in AD patients. However, it is unclear how processing of APP to generate Aβ corresponds with the age-dependent pattern of brain-regional neurodegeneration common in AD. We have previously shown that overexpression of BACE1, the primary β-secretase gene, in mice expressing an AD mutant form of APP leads to significantly elevated regional Aβ levels, which coincide with the regional pattern of Aβ deposition. In the current study, we have used our genomic-based β-secretase transgenic mice to determine how BACE1 regulates the spatial and temporal pattern of Aβ production throughout post-natal development. Specifically, we observed unique differences in the brain-regional expression pattern between neonatal and adult BACE1 transgenic mice. These alterations in the BACE1 expression profile directly corresponds with age-related differences in regional Aβ production and deposition. These studies indicate that modulation of BACE1 expression leads to dramatic alterations in APP processing and AD-like neuropathology. Furthermore, our studies provide further evidence that BACE1 plays a major role in the regulation of the APP processing pathway, influencing the agedependent onset of AD pathogenesis.

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Section: Discussionsupporting

confidence: 91%

Spatial and temporal control of age-related APP processing in genomic-based β-secretase transgenic mice

Chiocco

Lamb

2007

Neurobiology of Aging

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“…Brain extracts used in this assay were subsamples of those tested in the APP assay. ELISA was performed to quantitatively assay levels of A␤ 40 in different brain extract samples using an Immuno-Biological Laboratories kit that detects human as well as rodent A␤ (27713; Immuno-Biological Laboratories Company, Gunma, Japan), as described previously Basha et al, 2005). The number of samples tested were control and all drug treatments, n ϭ 9, except for 75 mg posiphen, wherein n ϭ 8.…”

Section: Methodsmentioning

confidence: 99%

The Experimental Alzheimer's Disease Drug Posiphen [(+)-Phenserine] Lowers Amyloid-β Peptide Levels in Cell Culture and Mice

Lahiri¹,

Chen²,

Maloney³

et al. 2006

J Pharmacol Exp Ther

120

133

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Major characteristics of Alzheimer's disease (AD) are synaptic loss, cholinergic dysfunction, and abnormal protein depositions in the brain. The amyloid ␤-peptide (A␤), a proteolytic fragment of amyloid ␤ precursor protein (APP), aggregates to form neuritic plaques and has a causative role in AD. A present focus of AD research is to develop safe A␤-lowering drugs. A selective acetylcholinesterase inhibitor, phenserine, in current human trials lowers both APP and A␤. Phenserine is dose-limited in animals by its cholinergic actions; its cholinergically inactive enantiomer, posiphen (ϩ)-[phenserine], was assessed. In cultured human neuroblastoma cells, posiphen, like phenserine, dose-and time-dependently lowered APP and A␤ levels by reducing the APP synthesis rate. This action translated to an in vivo system. Posiphen administration to mice (7.5-75 mg/kg daily, 21 consecutive days) significantly decreased levels of total APP (tissue mass-adjusted) in a dose-dependent manner. A␤ 40 and A␤ 42 levels were significantly lowered by posiphen (Ն15 mg/kg) compared with controls. The activities of ␣-, ␤-, and ␥-secretases were assessed in the same brain samples, and ␤-secretase activity was significantly reduced. Posiphen, like phenserine, can lower A␤ via multiple mechanisms and represents an interesting drug candidate for AD treatment.Alzheimer's disease (AD) is typified by progressive impairment in short-term memory and emotional disturbances that result from dysfunction and death of neurons in the hippocampus and associated regions of the limbic system and cerebral cortex. These aberrations are considered to result, in part, from microtubule-associated protein () tangles and abnormal aggregates of cytoskeletal proteins (Cairns et al., 2004), oxidative stress, and the overproduction and accumulation of amyloid-␤ peptide (A␤) in and surrounding neurons (Selkoe, 2005).This 39-to 43-amino acid peptide (molecular mass ϳ4.1 kDa) is a core constituent of amyloid plaques and results from two catalytic cleavages of the larger integral membrane protein, amyloid-␤ precursor protein (APP; ϳ110 -130 kDa), at the N terminus (␤-secretase) and C terminus (␥-secretase) of A␤ (Sambamurti et al., 2002;Lahiri et al., 2003b;Selkoe, 2005). Significant evidence indicates that A␤ changes conformation from a physiological to a pathological, fibrillar peptide form, which not only induces local structural disruption of synapses and neurite breakage but also results in cell death due to perturbed calcium homeostasis and oxidative stress. In addition, soluble aggregates of A␤ or A␤-derived diffusible ligands found in the brains of AD patients have been recently shown to target synapses (Gong et al., 2003) and play a role in inhibiting LTP (Walsh et al., 2002;LaFerla and Oddo, 2005). Conjointly, these studies point to the importance of A␤ in learning and memory, suggest a causative role of A␤ in AD pathophysiology, and thereby support its

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“…Moreover, alterations in this pathway have been widely shown to be related to congenital malformations [27]. Studies on prenatal manipulation of this pathway and its consequences for the offspring have analyzed behavioral, biometric, biochemical or gene expression parameters [28][29][30][31]. In our study, we aimed to assess the impact of hHcy on male offspring by methionine supplementation during pregnancy/ lactation in mice.…”

Section: Discussionmentioning

confidence: 99%

Hyperhomocysteinemia and Gestational Programming of Genes Involved in Alzheimer’s Disease Pathogenesis

Silva¹

2014

J Nutr Food Sci

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Sciencesda Silva et al., J Nutr Food Sci 2013, 4:1 http://dx.doi.org/10.4172/2155-9600.1000253 *Corresponding author: Vânia D'Almeida, R. Napoleão de Barros, nº 925, 3º andar, São Paulo-SP, Brazil, CEP: 04024-002, Brazil, Tel: 55-11-21490155; Fax: 55-11-55725092; E-mail: vaniadalmeida@uol.com AbstractMaternal hyperhomocysteinemia (hHcy) induced by a high methionine diet delays brain maturation and leads to impairment of learning performance in the offspring. Because methionine-homocysteine metabolism is related to the regulation of gene expression through one-carbon metabolism, we investigated whether maternal supplementation with methionine affects the expression of Adam10, Bace1, Bace2, Ps1, Ps2, Tace, App, and Tnf-α, genes related to Alzheimer's disease (AD) risk, in the offspring. Thirteen female mice were distributed into the following groups: a) standard diet and b) standard diet supplemented with 1% methionine in water. After birth, the offspring were organized into Control (CT) and Supplemented Diet (SD) groups, and at Postnatal Day (PND) 90, all animals were weighed and then euthanized. The homocysteine (Hcy) concentration in plasma was measured, and the whole brain was weighed and dissected, and the hippocampus used for gene expression analyses. A decrease in total body weight was found in SD group, but no differences in brain weight were observed. The maternal diet did not seem to affect the Hcy concentration of PND 90 offspring. No differences were found in the expression of AD related genes in the hippocampus (p>0.05). In conclusion, hHcy induced by methionine supplementation during pregnancy and lactation did not affect the expression of genes related to AD risk in the offspring.

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The Fetal Basis of Amyloidogenesis: Exposure to Lead and Latent Overexpression of Amyloid Precursor Protein and β-Amyloid in the Aging Brain

Cited by 329 publications

References 36 publications

Spatial and temporal control of age-related APP processing in genomic-based β-secretase transgenic mice

Spatial and temporal control of age-related APP processing in genomic-based β-secretase transgenic mice

The Experimental Alzheimer's Disease Drug Posiphen [(+)-Phenserine] Lowers Amyloid-β Peptide Levels in Cell Culture and Mice

Hyperhomocysteinemia and Gestational Programming of Genes Involved in Alzheimer’s Disease Pathogenesis

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