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. Author manuscript; available in PMC: 2013 Jun 24.
Published in final edited form as: J Alzheimers Dis. 2011;27(2):385–391. doi: 10.3233/JAD-2011-110785

Increased AβPP Processing in Familial Danish Dementia Patients

Shuji Matsuda a, Robert Tamayev a, Luciano D’Adamio a,b,*
PMCID: PMC3690758  NIHMSID: NIHMS480912  PMID: 21841249

Abstract

An autosomal dominant mutation in the BRI2/ITM2B gene causes Familial Danish Dementia (FDD). We have generated a mouse model of FDD, called FDDKI, genetically congruous to the human disease. These mice carry one mutant and one wild type Bri2/Itm2b allele, like FDD patients. Analysis of FDDKI mice and samples from human patients has shown that the Danish mutation causes loss of Bri2 protein. FDDKI mice show synaptic plasticity and memory impairments. BRI2 is a physiological interactor of amyloid-β protein precursor (AβPP), a gene associated with Alzheimer’s disease, which inhibits processing of AβPP. AβPP/Bri2 complexes are reduced in synaptic membranes of FDDKI mice. Consequently, AβPP metabolites derived from processing of AβPP by β-, α-, and γ-secretases are increased in Danish dementia mice. AβPP haplodeficiency prevents memory and synaptic dysfunctions, consistent with a role for AβPP-metabolites in the pathogenesis of memory and synaptic deficits. This genetic suppression provides compelling evidence that AβPP and BRI2 functionally interact. Here, we have investigated whether AβPP processing is altered in FDD patients’ brain samples. We find that the levels of several AβPP metabolites, including Aβ, are significantly increased in the brain sample derived from an FDD patient. Our data are consistent with the findings in FDDKI mice, and support the hypothesis that the neurological effects of the Danish form of BRI2 are caused by toxic AβPP metabolites, suggesting that Familial Danish and Alzheimer’s dementias share common pathogenic mechanisms.

Keywords: Alzheimer’s disease, amyloid-β protein precursor, BRI2, familial danish dementia

INTRODUCTION

Familial Danish Dementia (FDD) is caused by a 10-nucleotide duplication preceding the stop codon of the BRI2/ITM2B gene [1]. In normal individuals, BRI2 is synthesized as an immature type-II membrane protein (imBRI2) that is cleaved at the C-terminus by a pro-protein convertase to produce mature BRI2 (mBRI2) and a 23aa soluble C-terminal fragment (Bri23)[2]. However, in FDD patients, a longer C-terminal fragment, the ADan peptide [1], is generated from the Danish mutant protein (BRI2-ADan), which has amyloidogenic properties. ADan forms amyloid angiopathy in the small blood vessels and capillaries of the cerebrum, choroid plexus, cerebellum, spinal cord, and the retinas [1]. FDD patients also show diffuse brain atrophy, particularly in the cerebellum, cerebral cortex, and white matter, as well as the presence of very thin and almost demyelinated cranial nerves; neurofibrillary tangles are the major histological finding in the hippocampus [1].

We have generated and analyzed a mouse model of FDD that carries one wild type (WT) and one mutated Bri2 allele, like FDD patients. This model shows that memory loss in FDD is caused by loss of BRI2 function [3], and is supported by several lines of evidence: 1) FDDKI mice present reduced mBri2 levels (similar to what is seen in FDD human brains); 2) the reduction in BRI2 is accompanied by significant synaptic and memory deficits; 3) Bri2+/− mice present memory and synaptic plasticity deficits; 4) the memory deficits of FDDKI mice are prevented by expression of WT BRI2 in the forebrain [3–5].

Familial Alzheimer disease (FAD) cases are caused by autosomal dominant mutations in either amyloid-β protein precursor (AβPP) or in presenilins (PSEN1 and PSEN2) [6], which are key components of a multi-molecular complex with γ-secretase activity [7]. AβPP is normally sequentially cleaved by the β- and the γ-secretase. The gamma-cut yields the Aβ peptide, consisting of two major species of 40 and 42 amino acids (Aβ40 and Aβ42, respectively, of which Aβ42 has amyloidogenic properties) [8] and an intracellular product termed the AβPP intracellular domain (AID or AICD) that regulates cell death [9] and gene transcription [10]. It is believed that FAD mutations in either AβPP or PSEN1/2 favor the formation of the amyloidogenic Aβ42 peptide over the Aβ40 species. Compelling evidence indicates that BRI2 regulates processing of AβPP. BRI2 binds AβPP in the cellular compartments where AβPP is cleaved [11]. BRI2 binds to AβPP in the region that contains the cleavage sites for and interferes with the docking of γ-secretase to C99 [12]. In doing so, mBRI2 protects mAβPP from processing. The evidence that mutations in AβPP and in genes that regulate AβPP processing, such as presenilins and BRI2, cause dementias [2, 6, 11, 13–16], emphasizes the relevance of AβPP processing to AD pathogenesis. Loss of Bri2 function in FDDKI mice leads to dementia via deregulation of AβPP processing [17]. This mechanism presents strong analogies with the pathogenesis of classical FAD cases, where genes that, like BRI2, regulate AβPP processing (i.e., PSEN1/2) are mutated. Here we have investigated whether AβPP processing is also altered in FDD human cases.

MATERIAL AND METHODS

Human brain preparations for Western Blot and ELISA

100 mg of brains were homogenized in 1 ml of Hepes-sucrose buffer (20 mM Hepes/NaOH pH 7.4, 1 mM EDTA, 1 mM EGTA, 0.25 M sucrose) supplemented with protease inhibitors and phosphatase inhibitors. The post-nuclear supernatant (PNS) was prepared by precipitating the nuclei and debris by centrifuging the homogenates at 1000 g for 10 min. Twenty μg of each PNS were loaded on SDS-PAGE. PNS was cleared by centrifuging at 100,000 g for 45 min (soluble fraction). Soluble fractions were used for sAβPPα and sAβPPβ western blot and ELISA (IBL 11088 and 10321, respectively).

Aβ was extracted from the homogenates by either diethylamine or by formic acid. In diethylamine extraction, 100 μl of the above homogenates were mixed with 100 μl of DEA buffer (0.4% diethylamine and 100 mM NaCl), and homogenized with a Dounce homogenizer. Centrifuging at 100,000 g for 45 min cleared the mixture. The supernatant was neutralized with 1/10 volume of 0.5 M Tris/HCl pH 6.8. This corresponds to the soluble Aβ fraction. Insoluble Aβ was obtained with formic acid extraction. 200 μl of the above homogenates were mixed with 440 μl of formic acid, and sonicated on ice for 1 minute. Centrifuging at 100,000 g for 45 min cleared 400 μl of the sonicated homogenate. 210 μl of the cleared supernatant was neutralized with 4 ml of neutralization buffer (1 M Tris base, 0.5 M Na2HPO4, 0.05% NaN3, pH not adjusted). The extracted Aβ was measured using the ELISA kit for Aβ40 and Aβ42 (IBL 17713 and 17711, respectively).

Antibodies

The following antibodies and antibody beads were used: α-sAβPPα (IBL 11088); α-AβPP C-terminal fragments (CTF) (Invitrogen/Zymed 36-6900); the mouse monoclonal α-Tau antibodies DA9 (IgG1, raised against Tau residues 102–140) and PHF1 (IgG1, against pSer396/Ser404) were kindly provided by Dr. Peter Davies [18]. BRI2 antibody (recognizing amino acids 7–21 of human BRI2) was a generous gift from Dr. Haruhiko Akiyama [19].

Heat stable preparation

Brains were homogenized in 1 mL of Homogenizing Buffer TBS (10 mM TRIS, 140 mM NaCl, pH 7.4) plus Protease + Phosphastase inhibitors (Pierce). 40 microliter of 5M NaCl and 50 microliter of βME were added and samples were mixed and heated at 100°C for 15′. Samples were cooled in ice for 30′, vortexed and centrifuged for 10′ at 4°C at 20,000 g. The supernatant was collected and analyzed by western blot with the PHF1 antibody.

RESULTS AND DISCUSSION

Reduced mBRI2 and presence of tau aggregates in danish dementia

Analysis of brains from FDDKI mice and FDD patients has shown that the levels on mature BRI2 are significantly reduced as a consequence of the Danish mutation in the BRI2/ITM2B gene [3]. This data is confirmed by a further analysis of an FDD human brain compared to an age-matched normal control and brain samples isolated from the fronto-temporal region of two human sporadic AD cases (Fig. 1). The pattern seen in human brains is strikingly similar to that seen in transfected cells [3]. Normal and AD human brains showed predominantly a single BRI2 species (Fig. 2B), which corresponds to the mBRI2 protein seen in transfected cells, with a very faint upper band, which corresponds to the imBRI2 protein seen in transfected cells. The FDD brain sample showed two bands; the lower one co-migrated with the mBRI2 band detected in control samples and was reduced in quantity as compared to controls. The larger form, which is slightly higher than imBRI2 and is only detectable in FDD cases, represented ~50% of the total BRI2 protein and corresponds to the immature mutant protein, called BRI2-ADan (Fig. 1), seen in transfected cells. Unpublished data indicate that the mutant protein is largely targeted for lysosomal degradation rather than maturation.

Fig. 1.

Fig. 1

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Reduced mature BRI2 in the human FDD brain. Analysis of a brain lysates either from an FDD patient (FDD), an age-matched normal control (con.) and two sporadic AD cases (AD1 and AD2) shows that mBRI2 levels are significantly reduced in the Danish case as compared to the control and AD brains. Analysis of AβPP and AβPP-CTFs indicates no major differences in AβPP levels among the four samples. *Indicates a background band.

Fig. 2.

Fig. 2

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PHFs are detected in FDD and AD brains. Brain lysates (upper panel) and heat-stable samples (lower panel) either from an FDD patient (FDD), an age-matched normal control (con.) and two sporadic AD cases (AD1 and AD2) were analyzed by immunoblot using anti-total-tau (DA9, upper panel) and anti-phospho-tau (PHF1, lower panel) antibodies. PHF are clearly detectable in FDD, AD1 and AD2 but not in the age-matched normal control.

Senile plaques and neurofibrillary tangles characterize FDD patients. Neurofibrillary tangles represent intracellular bundles of self-assembled hyperphosphorylated tau proteins [20, 21] and abnormally phosphorylated tau aggregates into paired helical filaments (PHF). Analysis of total brain lysates shows that the FDD samples contained less total tau (Fig. 2, upper panel). However the significance of this finding is unclear. A tau signal of higher molecular weight is present in FDD and AD samples but not control brains. This band is compatible with aggregated tau species. To determine biochemically the presence of PHF-tau in brain samples, heat-stable preparations were analyzed with the PHF1 antibody raised against pSer396/Ser404 of tau. As shown if Fig. 2 (lower panel), tau immunoreactivity was detected in a broad molecular mass range of ~38 to more than 200 kDa in the two AD brains and in the FDD sample, but not in the control material. This is consistent with published reports indicating that the presence of neurofibrillary tangles characterizes FDD patients. Interestingly, lower total tau protein was observed in the FDD sample while PHF1 tau was increased. Whether this trait is the consequence of specific changes in FDD brains or whether the lower total tau levels reflect an artifact of this preparation remains to be determined.

Soluble and insoluble Aβ40 and Aβ42 are increased in the FDD patient

BRI2 maturation is critical for the regulation of AβPP processing and BRI2 inhibits processing of AβPP and its metabolites by all three secretases [11, 12, 15, 16]. The evidence that loss of Bri2 protein in FDDKI mice results in increased processing of AβPP supports this concept. Analysis of brain samples showed increased levels of sAβPPα and sAβPPβ in FDDKI mice as compared to WT animals. The increase in sAβPPα and sAβPPβ is due to augmented production, rather than reduced degradation and/or export of sAβPPα and sAβPPβ from the CNS to peripheral tissues, supporting the idea that cleavage of AβPP by both α- and β-secretase in augmented in FDDKI mice [17]. Loss of Bri2 also results in increased cleavage of C99 by γ-secretase as documented by the elevation of Aβ40, Aβ42, and AID levels in FDDKI samples [17]. These data are reminiscent of the data obtained in Bri2 haplodeficient and null mice [12], again underscoring the loss of function nature of the FDD mutation. In addition, γ-cleavage of APLP1, a member of the AβPP gene family that is processed by γ-secretase as well [22, 23] but does not interact with BRI2 [12], was not affected by the loss of Bri2 in FDDKI mice [17]. This is consistent with the proposition that BRI2 reduces γ-cleavage of AβPP-CTFs by hampering docking of the γ-secretase and not via inhibition of the enzymatic activity of γ-secretase [12]. Likewise, AβPP processing is also increased.

Given the reduction in mBRI2 levels in the human FDD samples, we asked whether the Danish mutation compromises the inhibitory effect of BRI2 on AβPP processing in human FDD patients as well. We compared an FDD human brain to the age-matched normal control and two sporadic AD human brain samples. The abundance and solubility of Aβ peptides are critical determinants of amyloidosis in Alzheimer’s disease (AD). Notably, Aβ42 co-deposits with ADan in FDD cases [24] and this co-localization in vivo may be triggered by interactions between ADan and Aβ peptides [25] in addition to an increase in the production of Aβ peptides. Hence, we compared levels of total soluble and insoluble Aβ40 and Aβ42 in the FDD versus the age-matched normal aging brain and the two AD samples using a sandwich enzyme-linked immuno assay (ELISA). The levels of soluble Aβ42 were increased in FDD and AD brains compared to aging brains (FDD versus Con., 11-fold increase; AD1 versus Con., 4-fold increase; AD2 versus Con., 14-fold increase, Fig. 3A). Similarly, insoluble Aβ42 was higher in FDD and AD brains (FDD versus Con., 125-fold increase; AD1 versus Con., 178-fold increase; AD2 versus Con., 272-fold increase, Fig. 3B). Comparable results were obtained for soluble Aβ40 (FDD versus Con., 27-fold increase; AD1 versus Con., 58-fold increase; AD2 versus Con., 706-fold increase, Fig. 3C) and insoluble Aβ40 (FDD versus Con., 38-fold increase; AD1 versus Con., 164-fold increase; AD2 versus Con., 1379-fold increase, Fig. 3D).

Fig. 3.

Fig. 3

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Aβ40 and Aβ42 levels are increased in FDD and AD brains. Measurements of soluble and insoluble Aβ42/40 (A, soluble Aβ42; B, insoluble Aβ42; C, soluble Aβ40; D, insoluble Aβ40) levels by ELISA in human brain samples from an age/matched normal control, one FDD patient and 2 AD cases (AD1 and AD2), demonstrates that soluble and insoluble Aβ42/40 levels are greatly increased in the FDD patient and AD cases.

Increased levels of soluble AβPPβ and AβPPα in danish dementia

As cited above, processing of AβPP by both α- and β-secretase is augmented in FDDKI and Bri2−/− mice. This is reflected by the increased levels of sAβPPα and sAβPPβ in FDDKI and Bri2−/− brains [12, 17] and by the increased production of sAβPPα in the supernatant of dermal fibroblasts derived from FDDKI mice [17]. We tested the FDD human brain and the age-matched normal control brain sAβPPβ using an ELISA method. As shown in Fig. 4A, the level of sAβPPβ was 2.7-fold higher in the FDD sample as compared to age-matched control. Analysis of sAβPPα in the CNS also supports the claim that AβPP cleavages are increased in FDD. In fact, an ELISA test showed that the levels of sAβPPα were increased 5-fold in an FDD brain when compared to the age-matched control (Fig. 4B). Western blot analysis with an antibody specific for the C-terminal epitope of sAβPPα confirmed this observation (Fig. 4C).

Fig. 4.

Fig. 4

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sAβPPα and sAβPPβ levels are augmented in the FDD human sample. Measurements of sAβPPβ (A) and sAβPPα (B) by ELISA in human brain samples from an age/matched normal control and one FDD patient suggests an increased processing of AβPP by both β- and α-secretase in Danish dementia. C) Western blot analysis for sAβPPα shows higher level of sAβPPα in the FDD human brain as compared to the age/matched normal control.

Previous data had shown that loss of BRI2 function in Familial Danish and British dementia mice leads to synaptic plasticity deficits and memory impairments [3, 4]. Interestingly, transgenic mouse models of FDD, despite the considerable amyloidosis, do not show memory loss [26, 27]. Consistent with the proposed function of mBRI2, FDDKI mice show reduced levels of mBRI2 and increased processing of AβPP. Strikingly, AβPP haplodeficiency prevents memory and synaptic dysfunctions in FDDKI mice, supporting the claim that Danish dementia is mediated, like FAD, through toxic AβPP products [17]. Although the obvious candidate is Aβ42, the identity of this (these) toxic product(s) is still unknown and various AβPP-derived fragments, including AID/AICD [9, 28, 29] and sAβPPβ [30] have been implicated in neurodegenerative processes. Here we have analyzed a sample from a human case of FDD and compared it to an age-matched normal control, to determine whether alteration in AβPP metabolism can also be ascertained in human cases. Our data indicate that some AβPP-derived metabolites, specifically Aβ40, Aβ42, sAβPPβ and sAβPPα are 0augmented in the FDD s0000ample as compared to the age-matched control. The trend described in this manuscript is consistent with the data obtained with the mouse knock-in model of FDD and support the notion that AβPP processing is altered in Danish dementia [17]. Since altered AβPP processing in FDDKI mice is responsible for the synaptic dysfunction and the memory loss observed in these mice [17], our data would argue that a similar mechanism leads to the pathogenesis of dementia in FDD patients. It is possible that clearance of AβPP metabolites as well as nucleation of Aβ peptides together with ADan peptides may contribute to the increased levels of these metabolites. Although our data present no evidence supporting a role for ADan in synaptic plasticity and memory deficits, ADan may set off other clinical symptoms of FDD patients, such as cataracts, deafness and progressive ataxia, that are not replicated in FDDKI mice. It is worth noting that also Familial British Dementia (FBD) brains present lower levels of mBRI2 and that FBDKI mice have memory deficits [4]. Thus, it will be meaningful to determine whether AβPP processing is also altered in FBD patients and whether toxic AβPP metabolites play a role in memory loss in FBD as well.

In spite of the clarity of the findings here reported, these data should be interpreted cautiously because only one FDD and one age-matched control were analyzed. Unfortunately, we are unable to extend the experiments to more FDD and control cases because we have no access to these samples. Hopefully, the scientists that have access to material from the human FDD cases will find our work interesting and important to confirm or refute our results.

Acknowledgments

We thank Dr. Tamas Revesz for providing the human brains. This work was supported by grants from the Alzheimer’s Association (IIRG-09-129984 to L.D.), the Edward N. & Della L. Thome Memorial Foundation grant (to L.D.) and the National Institutes of Health (NIH; R01AG033007 to L.D.).

Footnotes

Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=920).

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