Self-administration of ethanol: towards the location of predisposing polygenes in quasi-congenic animal models.

Alcohol consumption by C57BL/6By background and BALB/cJ donor strains, and by two recently developed quasi-congenic QTL-introgression strains, which share about 96% of their genes with the background strain, was studied in a limited access paradigm. Alcohol and water were offered for 60 min per day using modified pipettes on a drinking cage. Increasing concentration of alcohol solutions, 3, 6, and 12%, were given for days 1-7, 8-14, and 15-22, respectively. Consumption of the 12% alcohol solution was highest in C57BL/6By (0.72 g/kg/h), lowest in BALB/cJ (0.14 g/kg/h). The B6.Cb4i5 beta 13 quasi-congenic strain, in spite of its genetic similarity to the C57BL/6By background strain, consumed significantly less alcohol (0.41 g/kg/h) than the background strain. The results suggest that polygenes that reduce alcohol consumption were introgressed from the BALB/cJ donor strain into the C57BL/6By background strain, and that the b4i5 series of the B6.C quasi-congenic QTL-introgression strains may be useful in mapping genes that influence alcohol-related behaviors. Locations of the introgressed candidate polygenes were tentatively identified by analyzing microsatellite maps of two of the quasi-congenic strains.

Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model.

Recent data suggest that cholesterol metabolism is linked to susceptibility to Alzheimer's disease (AD). However, no direct evidence has been reported linking cholesterol metabolism and the pathogenesis of AD. To test the hypothesis that amyloid beta-peptide (Abeta) deposition can be modulated by diet-induced hypercholesterolemia, we used a transgenic-mouse model for AD amyloidosis and examined the effects of a high-fat/high-cholesterol diet on central nervous system (CNS) Abeta accumulation. Our data showed that diet-induced hypercholesterolemia resulted in significantly increased levels of formic acid-extractable Abeta peptides in the CNS. Furthermore, the levels of total Abeta were strongly correlated with the levels of both plasma and CNS total cholesterol. Biochemical analysis revealed that, compared with control, the hypercholesterolemic mice had significantly decreased levels of sAPPalpha and increased levels of C-terminal fragments (beta-CTFs), suggesting alterations in amyloid precursor protein processing in response to hypercholesterolemia. Neuropathological analysis indicated that the hypercholesterolemic diet significantly increased beta-amyloid load by increasing both deposit number and size. These data demonstrate that high dietary cholesterol increases Abeta accumulation and accelerates the AD-related pathology observed in this animal model. Thus, we propose that diet can be used to modulate the risk of developing AD.

A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease.

Clinical, epidemiological, and laboratory studies suggest that cholesterol may play a role in the pathogenesis of Alzheimer's disease (AD). Transgenic mice exhibiting an Alzheimer's beta-amyloid phenotype were treated with the cholesterol-lowering drug BM15.766 and tested for modulation of beta-amyloid levels. BM15.766 treatment reduced plasma cholesterol, brain Abeta peptides, and beta-amyloid load by greater than twofold. A strong, positive correlation between the amount of plasma cholesterol and Abeta was observed. Furthermore, drug treatment reduced the amyloidogenic processing of the amyloid precursor protein, suggesting alterations in processing in response to cholesterol modulation. This study demonstrates that hypocholesterolemia is associated with reduced Abeta accumulation suggesting that lowering cholesterol by pharmacological means may be an effective approach for reducing the risk of developing AD.

Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer's disease.

Mutations in the amyloid precursor protein (APP) and presenilin-1 and -2 genes (PS-1, -2) cause Alzheimer's disease (AD). Mice carrying both mutant genes (PS/APP) develop AD-like deposits composed of beta-amyloid (Abeta) at an early age. In this study, we have examined how Abeta deposition is associated with immune responses. Both fibrillar and nonfibrillar Abeta (diffuse) deposits were visible in the frontal cortex by 3 months, and the amyloid load increased dramatically with age. The number of fibrillar Abeta deposits increased up to the oldest age studied (2.5 years old), whereas there were less marked changes in the number of diffuse deposits in mice over 1 year old. Activated microglia and astrocytes increased synchronously with amyloid burden and were, in general, closely associated with deposits. Cyclooxygenase-2, an inflammatory response molecule involved in the prostaglandin pathway, was up-regulated in astrocytes associated with some fibrillar deposits. Complement component 1q, an immune response component, strongly colocalized with fibrillar Abeta, but was also up-regulated in some plaque-associated microglia. These results show: i) an increasing proportion of amyloid is composed of fibrillar Abeta in the aging PS/APP mouse brain; ii) microglia and astrocytes are activated by both fibrillar and diffuse Abeta; and iii) cyclooxygenase-2 and complement component 1q levels increase in response to the formation of fibrillar Abeta in PS/APP mice.

Lack of nigral pathology in transgenic mice expressing human alpha-synuclein driven by the tyrosine hydroxylase promoter.

alpha-Synuclein has been identified as a major component of Lewy body inclusions, which are one of the pathologic hallmarks of idiopathic Parkinson's disease. Mutations in alpha-synuclein have been found to be responsible for rare familial cases of Parkinsonism. To test whether overexpression of human alpha-synuclein leads to inclusion formation and neuronal loss of dopaminergic cells in the substantia nigra, we made transgenic mice in which the expression of wild-type or mutant (A30P and A53T) human alpha-synuclein protein was driven by the promoter from the tyrosine hydroxylase gene. Even though high levels of human alpha-synuclein accumulated in dopaminergic cell bodies, Lewy-type-positive inclusions did not develop in the nigrostriatal system. In addition, the number of nigral neurons and the levels of striatal dopamine were unchanged relative to non-transgenic littermates, in mice up to one year of age. These findings suggest that overexpression of alpha-synuclein within nigrostriatal dopaminergic neurons is not in itself sufficient to cause aggregation into Lewy body-like inclusions, nor does it trigger overt neurodegenerative changes.

Modulation of A(beta) peptides by estrogen in mouse models.

Clinical studies have shown that estrogen deprivation through menopause is a risk factor in both the initiation and progression of Alzheimer's disease (AD) and that estrogen replacement therapy may be protective. One of the major pathological features in the human AD brain is the senile plaque, a proteinaceous structure composed mainly of heterogeneous peptides collectively known as A-beta (A(beta)). In vitro studies have linked estrogen with A(beta) modulation, suggesting that one-way that estrogen depletion at menopause may exacerbate the features of AD is through A(beta) accumulation. To test this, two studies were performed on transgenic models of amyloidosis. Firstly, transgenic mice without detectable amyloid aggregates were subjected to ovariectomy and estradiol supplementation, and A(beta) levels were assessed. Secondly, the effects of estrogen modulation were assessed in mice at an age when plaques would be forming initially. Overall, A(beta) levels were higher in estrogen-deprived mice than intact mice, and this effect could be reversed through the administration of estradiol. These data suggest that, in vivo, estrogen depletion leads to the accumulation of A(beta) in the CNS, which can be reversed through replacement of estradiol. These results provide evidence that post-menopausal estrogen depletion may be linked to an increased risk of AD through A(beta) modulation.