In situ hybridization analysis of presenilin 1 mRNA in Alzheimer disease and in lesioned rat brain

Abstract

Presenilin-1 (PS-1) gene mutations are responsible for the majority of the early onset familial forms of Alzheimer disease (AD). Neither PS-1's anatomic distribution in brain nor expression in AD have been reported. Using in situ hybridization in the rat forebrain, we show that PS-1 mRNA expression is primarily in cortical and hippocampal neurons, with less expression in subcortical structures, in a regional pattern similar to APP695. Excitotoxic lesions lead to loss of PS-1 signal. A neuronal pattern of expression of PS-1 mRNA was also observed in the human hippocampal formation. AD and control levels did not differ. PS-1 is expressed in brain areas vulnerable to AD changes more so than in areas spared in AD; however, PS-1 expression is not sufficient to mark vulnerable regions. Collectively, these data suggest that the neuropathogenic process consequent to PS-1 mutations begins in neuronal cell populations.Alzheimer disease (AD) is a widespread and devastating neurodegenerative disorder that manifests itself as a progressive and irreversible decline in cognitive abilities associated with the development of neurofibrillary tangles and senile plaques in a distinctive pattern in the brain. The underlying causes and pathophysiologic mechanisms of AD remain unknown. Molecular analysis in recent years has suggested that the causes may be heterogeneous. There are now four well established genes associated with AD. Inheritance of a common allele of the apolipoprotein E gene, apoE 4, is a risk factor for late onset (Ͼ60 years old) AD (1). The other three genes are causative and lead to autosomal dominant forms of the disease with fairly early ages of onset (Ͻ60 years, frequently even in the 40s). Mutations in the amyloid precursor protein (APP) (2) account for a small percentage of early onset familial AD cases (3). The majority of early onset familial AD appears to be due to mutations in two recently discovered genes, presenilin 1 (PS-1) located on chromosome 14 (4), which is responsible for AD in multiple pedigrees, and PS-2, located on chromosome 1, which is responsible for AD in the well studied Volga German families (5, 6). Twenty-four mutations have already been discovered in PS-1 in 52 pedigrees, and two mutations in PS-2 have been described (4-13). PS-1 and PS-2 are 67% identical to one another, and also share marked homology of approximately 50% identity with the Caenorhabditis elegans gene product . The predicted amino acid sequence of PS-1 suggests a protein structure that is serpentine, with multiple hydrophilic loops separated by transmembrane domains.The normal role of the PS-1 gene product is unknown, and its role in the pathophysiology of AD remains speculative. PS-1 mRNA is ubiquitously expressed, but detailed knowledge of its expression and localization in the brain is not yet available. Our initial studies suggest a neuronal localization in normal human brain (15). We have now used oligonucleotide probes to examine AD and control brain expression of PS-1 mRNA. In addition, a mouse homologue o...

Impact of Aging: Sporadic, and Genetic Risk Factors on Vulnerability to Apoptosis in Alzheimer's Disease

“…Human APP or PS1 revealed a similar expression pattern in mice as did endogenous APP or PS1 with a higher expression level in the brain than in nonneuronal cells (data not shown). A comparable expression pattern has also been found in man (Arai et al, 1991;Page et al, 1996).…”

“…Currently, no clear evidences for a predominant expression of APP or PS1 in the affected neurons, which might contribute to the cell type-specific vulnerability, have been provided. Several brain regions (e.g., hippocampus and cerebellum) express high levels of APP or PS1 within their neurons (Arai et al, 1991;Page et al, 1996;Mathews et al, 2000) but are affected differently by neurodegeneration. Based on these findings, we investigated the vulnerability of specific subgroups of peripheral Alzheimer's cells to cell death and the susceptibility pattern in sporadic and familial forms of the disease.…”

Induction of the Cholesterol Transporter ABCA1 in Central Nervous System Cells by Liver X Receptor Agonists Increases Secreted Aβ Levels

“…The anatomical pattern of ABCA1 in mice expression closely matches the regional expression of the genes required for A␤ generation: APP, presenilin-1, and BACE (25,56). Although each of these genes is expressed at high levels in cortical and limbic areas that develop senile plaques in human AD, high expression is also seen in the cerebellum, which does not develop significant amyloid deposition, indicating that other region-specific factors are necessary for plaque formation.…”

“…In Situ Hybridization-Unilateral hippocampal AMPA lesions were performed in four mice according to published procedures (25), and the mice were sacrificed by cervical dislocation at 1, 3, 7, and 11 days post-surgery. The brains were removed under ether anesthesia and sectioned coronally or sagitally at 16 m on a cryostat onto sterile Probe-On Plus slides (Fisher Scientific).…”

Evidence that Enzyme Processivity Mediates Differential Aβ Production by PS1 and PS2

“…PS1 and PS2 exhibit similar expression levels and a highly overlapping expression pattern throughout both the rat and human adult brain, as well as peripheral tissues [19-24]. One possible explanation is that the difference in Aβ production is due to a mechanistic difference in the way that PS1 and PS2 recognize and/or cleave APP substrate.…”