Molecular signatures of neurodegeneration in the cortex of PS1/PS2 double knockout mice
© Mirnics et al; licensee BioMed Central Ltd. 2008
Received: 25 June 2008
Accepted: 03 October 2008
Published: 03 October 2008
Familial Alzheimer's disease-linked variants of presenilin (PSEN1 and PSEN2) contribute to the pathophysiology of disease by both gain-of-function and loss-of-function mechanisms. Deletions of PSEN1 and PSEN2 in the mouse forebrain result in a strong and progressive neurodegenerative phenotype which is characterized by both anatomical and behavioral changes.
To better understand the molecular changes associated with these morphological and behavioral phenotypes, we performed a DNA microarray transcriptome profiling of the hippocampus and the frontal cortex of the PSEN1/PSEN2 double knock-out mice and littermate controls at five different ages ranging from 2–8 months. Our data suggest that combined deficiencies of PSEN1 and PSEN2 results in a progressive, age-dependent transcriptome signature related to neurodegeneration and neuroinflammation. While these events may progress differently in the hippocampus and frontal cortex, the most critical expression signatures are common across the two brain regions, and involve a strong upregulation of cathepsin and complement system transcripts.
The observed neuroinflammatory expression changes are likely to be causally linked to the neurodegenerative phenotype observed in mice with compound deletions of PSEN1 and PSEN2. Furthermore, our results suggest that the evaluation of inhibitors of PS/γ-secretase activity for treatment of Alzheimer's Disease must include close monitoring for signs of calpain-cathepsin system activation.
Presenilins (PS) are highly homologous polytopic membrane proteins that play a critical role in intramembranous processing of amyloid precursor proteins (APP), leading to the production of Aβ peptides (for reviews, see [1–4]). Inheritance of mutations in PSEN1 and PSEN2, that encode PS1 and PS2, respectively, cause familial forms of Alzheimer's disease (FAD) [5, 6], and do so by elevating the ratio of Aβß42/Aβ40 peptides [7–10]. Hence, it has been argued that FAD-linked PS1 variants cause disease primarily through a gain of function mechanism. However, recent studies have shown that these PS variants also result in a significant loss of γ-secretase function that may critically contribute to the pathophysiology of FAD (for a review, see ).
Over the last several years we assessed the gene expression profiles of PSEN1 knockout mice and PSEN1 mutant transgenic animals, and have defined a set of PSEN1-dependent genes [12–15]. However, it is important to point out that due to redundant functions and distributions of PSEN1 and PSEN2 [16, 17], cortical PSEN1 ablation in mice results in only a limited phenotype. In contrast, forebrain PSEN1/PSEN2 double KO mice show a strong and progressive neurodegenerative phenotype which is characterized by both anatomical and behavioral changes [11, 18]. Although anatomical changes are not apparent at 2 months of age, these mice already show mild memory impairments at this age. The behavioral phenotype progresses with time and the mutant mice begin to exhibit excessive grooming behavior, increased stereotypy in the open field, and reduced latency in the rotarod test at the age of 6 months . The anatomical changes develop over time, and the progressive thinning of cortical layers becomes prominent by the age of 6 months.
To gain a better understanding of presenilin-dependent neurodegeneration in the cortex, we performed an expression profiling of the hippocampus (HC) and frontal cortex (FC) of mice with forebrain ablations of PSEN1 and PSEN2. We used DNA microarrays to analyze the transcriptome at five developmental time points. We chose to examine the temporal nature of gene expression changes because the PSEN1 allele is conditionally deleted by a CamKII-cre allele that promotes recombination of "floxed" loci first in the hippocampus, and then spreads throughout the entire forebrain. We focused our attention on the following questions: 1) what are the gene expression consequences of PSEN1/PSEN2 ablation; 2) do the altered genes share common functional characteristics; 3) how does gene expression change over time as a function of PSEN1/PSEN2 deletion; 4) are the molecular signatures of neurodegeneration similar in the HC and FC and 5) is presenilin-dependent molecular neurodegeneration progressing similarly in FC and HC?
Gene expression differences regardless of brain region or age
Differentially expressed gene groups between the PSKO and CNT mice regardless of age or brain region.
Gene expression differences in the frontal cortex (FC)
Gene expression differences in the hippocampus (HC)
Gene expression similarities and differences in the FC and HC of PSKO mice
To determine if this was a true upregulation in the PSKO samples or it represented a failure to downregulate expression levels as part of normal development, we examined the normal developmental expression levels of these genes in the CNT mice (Additional File 6). As the expression levels of all these genes were stable in the tested age range (2–8 months) in both the FC and HC, we can conclude that the observed overexpression is indeed a result of an active transcriptional upregulation in the PSKO brain samples.
Over the past few years, we have used gene microarray strategies to examine transcript levels in brains of mice with conditionally inactivated PSEN1 (cPS1 KO) alleles. While these studies have proven informative, redundant function and distribution of PSEN1 and PSEN2 in hippocampus and cortex [16, 17] has limited the interpretation of our findings. Indeed, while cPS1KO mice fail to exhibit any neuroanatomical or behavioral alterations [19, 20], cPS1KO mice on a PSEN2 KO background show a strong and progressive neurodegenerative phenotype that is characterized by both anatomical and behavioral changes [11, 18]. These animals do not exhibit anatomical changes at 2 months of age, yet show mild memory impairments at this age. The behavioral phenotypes progress over time and are paralleled by considerable cortical atrophy and neurodegeneration. In the present study, we performed expression profiling in order to develop an understanding of the mechanism(s) that might mediate these morphological and behavioral observations, and we now offer several novel insights. First, we show that simultaneous ablation of PSEN1 and PSEN2 leads to a wide variety of gene expression changes that progress over time. Second, the frontal cortex and hippocampus are both affected in PSKO brains, albeit by the notable difference that gene expression changes in the FC are characterized by elevated transcript levels, while the HC is mostly characterized by reduced transcript levels. Third, the transcriptome changes suggest a progressive neurodegenerative process with strong immune system activation. Fourth, based on the BioCarta pathway analysis, it appears that GABA-ergic neurons may be a preferential early target of the neurodegenerative events. Fifth, the Complement and Cathepsin systems appear to be critical contributors to neurodegeneration in both the hippocampus and frontal cortex.
One of the most intriguing findings of the manuscript is that transcript repressions dominate in the FC, while transcript inductions are the hallmark of the HC tissue. Although the most prominent presenilin deletion induced transcript changes may be different between these two brain regions, the deletion signature of the FC expression change was strong in HC and vice versa. We interpret these findings that the neurodegenerative events in FC lag behind of those in HC, suggesting that the early stages of degeneration are characterized by a strong, widespread repression of mRNA species. However, as the pathophysiological process proceeds, in addition to the transcript repression, a de novo inflammation-related transcript induction occurs, which becomes a dominant feature of a gene expression profile in the HC. Alternatively, the differential cytoarchitecture and molecular composition of FC and HC provide a differential framework for the adaptational responses of these two brain regions, and results in a different gene expression profile.
Presenilins associate with Aph1, Pen2 and Nicastrin in a large complex that mediates intramembranous, "γ-secretase"  proteolysis of a variety of type-I membrane proteins, including Notch, APP, E-cadherins, N-cadherins, and p75NTR, amongst others (reviewed by ). For most of these proteins, γ-secretase-mediated processing results in the generation of intracellular derivatives, termed ICDs, that have been shown to initiate complex signaling cascades, including those involved in cell adhesion, lateral inhibition of cell fate decisions, neurotrophin signaling and cell differentiation [22, 23]. It has also become increasingly evident that PS have functions that go beyond their role as the catalytic entity of γ-secretase activity. For example, PS located in the endoplasmic reticulum (ER) and Golgi apparatus regulate calcium homeostasis , findings that may be equally relevant for neurodegeneration observed in the PSKO mice. Not surprisingly, with increasing age, the PSKO mice develop striking neurodegeneration of the cerebral cortex and worsening impairments of memory and synaptic function . However, it is important to point out that gene expression changes arise before noticeable anatomical neurodegeneration. The progressive gene expression changes that we observed in both hippocampus and frontal cortex also appear to suggest that the cortical GABA-ergic interneurons may be one of the early targets of neurodegeneration mediated by the ablation of PSEN genes. As the GABA-ergic system has a strong influence on cognitive behaviors [25, 26], the expression changes in interneurons are likely to be related to the altered cognitive processes reported in these mice. On the other hand, interneurons have been shown to exhibit enhanced vulnerability to various insults . These events likely result in necrosis-induced microglial activation, accompanied by overexpression of the complement system transcripts, leading to neuroinfammatory processes , thus further accelerating the neurodegenerative processes.
The mechanism(s) by which ablation of PSEN genes leads to neurodegeneration are not fully understood, but likely involve several converging pathways. In this regard, our dataset is highly informative: first, we observe a strong and progressive increase in expression of transcripts encoding molecules in the calpain-cathepsin system. These results confirm and expand the previously reported upregulation of Cathepsin S in these mice . Both calpains and cathepsins belong to the papain superfamily of cysteine proteases that are primarily localized in lysosomes and are critical for intracellular protein catabolism. Calpain-mediated extralysosomal release of cathepsins is a critical event in necrosis, and cathepsin inhibitors show strong neuroprotection in models of acute neuronal insults [30, 31]. Thus, we propose that neurodegeneration in these mice is a result of a progressive neuronal calpain-cathepsin system activation over time. How does loss of PS function lead to induction of the calpain-cathepsin system? We offer two proposals that are not mutually exclusive. In the first, we suggest that in the absence of PS/γ-secretase activity, extremely high levels of membrane-tethered stubs derived from type 1 membrane proteins hyperaccumulate in endosomal-lysosomal compartments, hence "saturating" those proteases that would otherwise be necessary for maintaining intracellular homeostasis. In this setting, the induction of the calpain-cathepsin system would thus reflect a compensatory mechanism. This hypothesis is consistent with the model that a function of PS/γ-secretase is to serve as a membrane-bound proteosome that promotes intramembranous proteolysis in order to enhance clearance of membrane-tethered stubs derived from ectodomain shedding of type 1 membrane proteins . Indeed, we have shown that cultured mammalian cells expressing dominant-negative PS1 variants harboring mutations at the critical aspartate 257 and 385 residues necessary for γ-secretase activity, exhibit unusual accumulations of distended intramembranous organelles resembling multivesicular bodies that are immunoreactive with antibodies specific for membrane-tethered stubs . The second model to explain our findings is in the absence of PS expression, the cell surface levels of receptors and ion channels in either pre- or postsynaptic membranes is altered in manner that gives rise to inappropriate signaling events and alterations in calcium homeostasis. In support of this notion, we  and others  have shown that cells that express dominant-negative forms of PS1 or that lack PSEN alleles, respectively, exhibit elevated levels of a variety of type I membrane proteins and their membrane-tethered stubs.
Inhibition of PS/γ-secretase activity has been debated as a promising therapeutic strategy for treatment of Alzheimer's Disease [35, 36]. In this context, our results offer a cautionary note and suggest that the preclinical evaluation of such agents should include close monitoring for signs of calpain-cathepsin system activation, and development of a peripheral tissue assays on the complement-cathepsin system expression as informative tools for assessment of potential adverse effects that may also be present is the CNS.
A. Experimental animals
To generate forebrain-specific PS conditional double knockout (PSKO) mice, we crossed floxed PS1 (fPS1), αCaMKII-Cre transgenic [19, 37, 38] and PS2-/-  mice together to obtain fPS1/fPS1;αCaMKII-Cre;PS2-/- mice. All experimental procedures were reviewed and approved by Institutional Animal Care and Use Committee (IACUC) of the University of Chicago (Protocol #s 71434 and 70958).
B. Sample preparation and hybridization
Hippocampi and frontal cortices were rapidly dissected and frozen on dry ice and stored at -80°C until RNA isolation. Total RNA was isolated using the Trizol reagent. RNA quality was assessed using the Agilent Bioanalyzer. All samples reported an RNA Integrity Number (RIN) > 8.0. Reverse transcription, in vitro transcription and fragmentation were performed according to manufacturer's recommendation http://www.affymetrix.com. FC and HC samples for microarray analysis were generated by pooling RNA from 3 animals from appropriate genotypes and ages. Samples were hybridized onto MG_430 mouse Affymetrix GeneChips. Microarrays were considered for use only if the average 3':5' ratio for GAPDH and actin did not exceed 1:1.2. Segmentation of scanned microarray images was performed by MAS5. Determination of expression levels and scaling were performed using gcRMA in GenePattern .
C. Data analysis
Identification of differentially expressed genes
i) Comparison of all KO animals to matched WT regardless of age or brain region. We identified genes as differentially expressed in the PSKO samples showed a pairwise difference > 50% (|ALR| > 0.585) at p < 0.05 to the matched WT controls. In this comparison a matched pairwise comparison eliminates the effects that are due to robust differences in the developmental age and brain region.
ii) Comparison of all HC KO animals to matched HC WT . We identified genes as differentially expressed in the HCKO samples showed a pairwise difference > 50% (|ALR| > 0.585) at p < 0.05 in the matched WT controls. In this comparison a matched pairwise comparison eliminated the effects due to developmental age.
iii) Comparison of all FC KO animals to matched FC WT . The comparison was performed in a similar fashion to that described for the HC samples.
These analyses were performed on the whole dataset using GSEA 2.0  and the preset pathways from BioCarta (ref). Enrichment in a pathway was considered significant if it reached a p < 0.01 at a q < 0.05 (FDR < 5%).
Correlations were calculated using Pearson r value for the log2 ratios between the two compared conditions.
Two-way clustering (sample and gene vectors) was performed on gcRMA generated log2-transformed expression levels using Euclidian distance in GSEA.
The gcRMA normalized microarray dataset, together with the previous PS1 KO and TG datasets [12–15] is available for download from http://mirnicslab.vanderbilt.edu/mirnicslab. Forthermore, the data will be deposiet in a MIAME/MGED format into the NCBI Gene Expression Omnibus database at the time of publication.
D. Western blots
A new set of control and experimental animals was used in this study. 100 ug of cortical brain homogenate was run on 12% SDS-PAGE under reducing conditions, transferred to nitrocellulose and probed for C1q (1:800). Membranes were stripped and re-probed for Cathepsin D (1:10,000) and tubulin (loading control). For each, membranes were blocked with 5% milk in tris-buffered saline with 0.1% tween-20 (TBST), incubated with primary antibody overnight at 4°C, washed and incubated in HRP-conjugated secondary antibody for 1 hour at room temperature. Blots were exposed using ECL substrate and a Chemidoc XRS imager (Bio-Rad). Cathepsin D antibody  was obtained from Dr. Ralph Nixon (New York University), while C1q antibody [43, 44] was provided by Dr. Andrea J. Tenner (U of California at Irvine). Molecular weights of Ctsd species correlate best to active intermediate (48 kD) and mature heavy chain (34 kD) .
We are thankful to Mrs. A. Bedison and Mr. T. Unger for outstanding technical assistance with sample preparation and handling. The C1q and cathepsin D antibodies we used were a generous gift by Dr. Andrea Tenner (University of California, Irvine) and Dr. Ralph Nixon (Nathan Kline Institute, NY), respectively. This work was supported by NIH R01 AG027854 (SSS, KM) and Ellison Medical Foundation (SSS). Salary support to MK was provided by K02 MH070786.
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