Thursday, April 07, 2011

Altheimer's, livers, highway exhaust

I saw these two snippets, and present them here, together:

1. Freeway air pollution linked to brain damage in mice (Apr 7, Louis Sahagun, LA Times) Excerpt: 
"It is well known that air pollution from cars and trucks on Southern California freeways -- a combination of soot, pavement dust and other toxic substances -- can cause respiratory disease, heart attacks, cancer and premature death.

Now, exposure to pollution particles roughly one-thousandth the width of a human hair has been linked to brain damage in mice, including signs associated with memory loss and Alzheimer’s disease, according to a USC study in the journal Environmental Health Perspectives.

In a statement, senior author Caleb Finch, an expert on the effects of inflammation and holder of USC's ARCO/William F. Kieschnick Chair in the Neurobiology of Aging, said “You can’t see them, but they are inhaled and have an effect on brain neurons that raises the possibility of long-term brain health consequences of freeway air.”
Lead author, Todd Morgan. 

A lot of whatever the body takes in and can't use to sustain itself, gets dismantled in the liver, right?

2. Sutcliffe, J. G., Hedlund, P. B., Thomas, E. A., Bloom, F. E. and Hilbush, B. S. (2011), Peripheral reduction of β-amyloid is sufficient to reduce brain β-amyloid: Implications for Alzheimer's disease. Journal of Neuroscience Research, 89: n/a. doi: 10.1002/jnr.22603. (Open access for now) 

Abstract:  (my bold)
"Three loci that modify β-amyloid (Aβ) accumulation and deposition in the brains of a mouse model of Alzheimer's disease have been previously described. One encompasses the Psen2 gene encoding presenilin 2, a component of the γ-secretase activity responsible for generating Aβ by proteolysis. We show that the activity of mouse Psen2, as measured by levels of mRNA accumulation, unexpectedly is heritable in the liver but not the brain, suggesting liver as the origin of brain Aβ deposits. Administration of STI571, a cancer therapeutic that does not cross the blood–brain barrier, reduced accumulation of Aβ in both the blood and the brain, confirming brain Aβ's peripheral origin and suggesting that STI571 and related compounds might have therapeutic/prophylactic value in human Alzheimer's disease. The genes Cib1 and Zfhx1b reside within the other modifier loci and also exhibit heritable expression in the liver, suggesting that they too contribute to Aβ accumulation. © 2011 Wiley-Liss, Inc.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the age-dependent deposition of β-amyloid (Aβ) within vulnerable regions of the brain, particularly the frontal cortex and hippocampus (Terry, 2006). Aβ has a pathogenic effect, leading to progressive neuronal loss that causes deterioration of the ability of those brain regions to orchestrate both higher order and basic neural processes. Some forms of human AD are highly heritable, caused by rare variations in genes that encode proteins that are associated with both familial and sporadic forms of this neurodegenerative disorder and play central roles in the initiation of the disease process. One of these encodes the amyloid precursor protein (APP; Tanzi, 1989), a membrane protein whose biochemical function is at present unknown. APP is a substrate for proteolysis by several endogenous proteases, liberating proteolytic fragments of various structures. Proteolysis of APP by β-secretase generates a fragment that can subsequently serve as a substrate for cleavage by γ-secretase at multiple adjacent positions within the precursor to form Aβ isoforms ranging from 37 to 43 amino acid residues. The 42-residue species is thought to be the most pathogenic (Wolfe, 2006) and forms oligomeric structures, which, in addition to depositing in plaques in the AD-affected brain, are thought to cause cognitive deficits (Barten and Albright, 2008). AD-predisposing variations in APP cluster in the vicinity of the proteolytic cleavage sites, affecting the rate at which pathogenic Aβ fragments are generated, their stability, and their ability to form oligomers (Selkoe, 2001). Individuals inheriting such APP variations usually show signs of AD in their 50s, whereas sporadic AD is not common until individuals reach their 70s (Waring and Rosenberg, 2008). Rare variations in two other genes, Presenilin 1 and Presenilin 2, also confer high risk for early-onset AD. These two genes encode independent proteins of similar structures that function as part of the γ-secretase protein complex (Wolfe, 2006). As a consequence of these genetic observations and considerable experimentation, the etiologic model that has emerged holds that biochemical events that increase the production and accumulation of Aβ, particularly Aβ1–42, accelerate the onset and progression of AD.
Transgenic mouse models have been developed that recapitulate critical features of human AD. In the R1.40 model, expression of a human APP transgene carrying the so-called Swedish mutations (K670N, M671L, variations that predispose those humans that inherit this mutant gene to develop early-onset AD) is driven from the natural human APP promoter (Kulnane and Lamb, 2001). Congenic lines were derived from the R1.40 model on the C57Bl/6 (B6) and DBA/2 (D2) backgrounds (Lehman et al., 2003). Although these two transgenic strains produced the same amount of APP precursor (indicating that the transgene was expressed comparably in the two strain backgrounds), B6s accumulated more Aβ than D2s, as measured by ELISA on brain homogenates and plasma at 21 and 60 days and developed amyloid deposits characteristic of human AD at 13.5 months, whereas the D2s were protected (no deposits at 2 years). This indicated that there were genetic differences that distinguish B6 and D2 mice and that modify the development of AD-like pathology, most likely by influencing the accumulation of the pathogenic substance Aβ (Lehman et al., 2003). The identities of the modifier genes might suggest therapeutic or prophylactic modalities that would mimic the modifier effect and delay or prevent the emergence of AD pathology.
To assign the modifying genes to chromosomal intervals (quantitative trait loci; QTLs), Ryman and colleagues (2008) analyzed Aβ accumulation in the brains of 516 F2 mice from a B6/D2 intercross population and mapped three modifying loci, assigned to broad regions centered on the following positions: chromosome 1, 182.049374 megabases (Mb); chromosome 2, 41.216315 Mb; and chromosome 7, 63.680922 Mb."

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