A novel mouse model of dementia implicates beta-secretase, Thr668 of APP, and Tau in the pathogenesis of Alzheimer's Disease
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Familial Alzheimer's disease (AD), Danish (FDD) and British Dementias (FBD) are autosomal dominant diseases defined by the presence of neurodegeneration, extra cellular amyloid plaques, and intracellular neurofibrillary tangles. The current pathogenic theory for all 3 is the amyloid cascade hypothesis, which states that the accumulation of amyloid triggers tauopathy, neurodegeneration, and cognitive and behavioral changes. This theory, however, has been studied using transgenic models, which are able to reproduce the amyloidosis. D'Adamio's lab created and began characterizing a model of FDD, called FDDKI, which is a knock-in model of Familial Danish Dementia, with the identical mutation in the BRI2/ITM2b gene as the human disease, which makes it genetically congruous model. This mouse model is heterozygous for the mutation, having the mutation in only one allele of Bri2, which is exactly what is seen in the human disease. This model does not show any amyloid lesions, however, these mice have full blown memory and synaptic transmission deficits, consequently refuting the amyloid cascade hypothesis. The FDDKI mice show a large reduction of mature Bri2 in synapses, showing a loss of Bri2 function. The current known role of Bri2 is the inhibition of processing of APP, by preventing the interaction between the secretases that cleave APP and APP. We tested this loss-of-function hypothesis genetically and found that the deficits were directly linked to the amyloid precursor protein (APP), the transmembrane protein whose overexpression or mutations lead to early onset AD. Cleavage of APP first by beta- or alpha-secretase, followed by cleavage by the gamma-secretase complex leads to the formation of Abeta40 and 42, of which Abeta-42 is the main component leading to plaque formation. This directly links Bri2, the protein mutated in FDD and FBD, to AD, making it another variant of AD. Further analysis showed that inhibiting beta-secretase, but not gamma-secretase, rescued the memory deficits and synaptic plasticity defects found in the FDDKI mice. This implicates sAPPbeta and/or beta-CTF, products of the beta-cleavage of APP, in the pathogenesis of FDD and consequently AD, rather than Abeta, which is derived from the gamma-cleavage. Furthermore, reconstituting Bri2, both genetically with the full protein and pharmacologically with the active amino acids of Bri2 that inhibit the processing of APP also abolished the memory defects in the mice. AD patients have an increased phosphorylation of Thr668 of APP. This residue also has a role of controlling certain interactions between APP and some binding partners. This role is mediated by the phosphorylation/dephosphorylation of the threonine, so a knock-in model mutating the threonine to an alanine was created in the D'Adamio lab. This single point mutation in FDDKI mice leads to complete abolishment of the memory deficits and synaptic plasticity deficits found in the FDD KI mice. Finally, we decided to look at the role of tau in the generation of the memory deficits in the FDDKI mice. The role of tau is unclear, as we do not see changes in levels of phosphorylation nor do we see neurofibrillary tangles, both features of AD and FDD patients, however, we see that low levels of tau lead to memory deficits; when you have both low levels of Tau, and low levels of Bri2, as in the FDDKI mice, the memory and synaptic deficits in both are abolished, suggesting a functional interaction between Bri2 and Tau. All these data combined show that FDD and AD have a multifaceted mechanism involving APP, Bri2, beta-secretase, and tau. Further studies of the FDDKI mice will shed more light into the mechanisms of AD and potential therapeutic options, such as Bri2-derived peptides, inhibiting Thr-668 residue on APP and/or its phosphorylation, and specific inhibitors of the interaction between beta-secretase and APP.