Abstract
Mutations in BRI2/ITM2b genes cause Familial British and Danish Dementias (FBD and FDD), which are pathogenically similar to Familial Alzheimer Disease (FAD). BRI2 inhibits processing of Amyloid precursor protein (APP), a protein involved in FAD pathogenesis. Accumulation of a carboxyl-terminal APP metabolite –β-CTF- causes memory deficits in a knock-in mouse model of FDD, called FDDKI. We have investigated further the pathogenic function of β-CTF studying the effect of Aph1B/C deletion on FDDKI mice. This strategy is based on the evidence that deletion of Aph1B/C proteins, which are components of the γ-secretase that cleaves β-CTF, results in stabilization of β-CTF and a reduction of Aβ. We found that both the FDD mutation and the Aph1B/C deficiency mildly interfered with spatial long term memory, spatial working/short-term memory and long-term contextual fear memory. In addition, the Aph1BC deficiency induced deficits in long-term cued fear memory. Moreover, the two mutations have additive adverse effects as they compromise the accuracy of spatial long-term memory and induce spatial memory retention deficits in young mice. Overall, the data are consistent with a role for β-CTF in the genesis of memory deficits.
Highlights
Amyloid precursor protein (APP) plays a central role in the pathogenesis of both sporadic and familial AD
Analysis of the time spent traveling at speed greater than 50 mm/s yielded significant main effects for day, F(2, 138) = 136.2, p < 0.0001, and for genotype, F(3, 69) = 3.97, p < 0.05, but no significant day × genotype interaction, F(6, 138) = 0.95, p = 0.4583, and showed that FDDKI mice spent more time traveling at speed greater than 50 mm/s than wild type (WT) mice on all three days (p
Because of the uncertainty concerning the pathogenic biochemical mechanisms of AD and related dementias, and considering that to improve the quality of life of AD patients -and caregivers- we need to either reverse or slow down the progression of the clinical symptomatology, we focused our analysis on learning and memory in our animal model of disease
Summary
APP plays a central role in the pathogenesis of both sporadic and familial AD. APP mutations that alter APP processing either protect from sporadic AD or cause familial AD; mutations in genes that regulate APP processing -such as PSENs and BRI2/ITM2B- cause FAD, FBD and FDD [1,2,3,4,5,6,7,8,9,10,11,12].As briefly mentioned above, mutations in BRI2/ ITM2B cause the AD-like autosomal dominant FBD and FDD [5, 7]. In FBD patients, a point mutation at the stop codon of BRI2 results in a read-through of the 3’-untranslated region and the synthesis of a BRI2 molecule containing 11 extra amino acids at the COOH terminus. FDD is caused by a10- nucleotide duplication before the stop codon of the BRI2 gene, which leads to the synthesis of a longer (277 amino acids) mutant protein [7, 15]. Convertase-mediated processing of the Danish mutant protein generates a longer C-terminal fragment, called ADan, and a normal mBRI2 polypeptide. Both ABri and ADan are deposited as amyloid fibrils. FBD and FDD patients present cognitive dysfunctions and neuropathology including neurodegeneration, amyloid, and neurofibrillary tangles [7, 15,16,17], which are similar to those of Alzheimer’s patients
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