Modeling familial British and Danish dementia

Familial British dementia (FBD) and familial Danish dementia (FDD) are two autosomal dominant neurodegenerative diseases caused by mutations in the BRI ( 2 ) gene. FBD and FDD are characterized by widespread cerebral amyloid angiopathy (CAA), parenchymal amyloid deposition, and neurofibrillary tangles. Transgenic mice expressing wild-type and mutant forms of the BRI(2) protein, Bri ( 2 ) knock-in mutant mice, and Bri ( 2 ) gene knock-out mice have been developed. Transgenic mice expressing a human FDD-mutated form of the BRI ( 2 ) gene have partially reproduced the neuropathological lesions observed in FDD. These mice develop extensive CAA, parenchymal amyloid deposition, and neuroinflammation in the central nervous system. These animal models allow the study of the molecular mechanism(s) underlying the neuronal dysfunction in these diseases and allow the development of potential therapeutic approaches for these and related neurodegenerative conditions. In this review, a comprehensive account of the advances in the development of animal models for FBD and FDD and of their relevance to the study of Alzheimer disease is presented

Caspase-9 mediates synaptic plasticity and memory deficits of Danish dementia knock-in mice: caspase-9 inhibition provides therapeutic protection

Background: Mutations in either Aβ Precursor protein (APP) or genes that regulate APP processing, such as BRI2/ITM2B and PSEN1/PSEN2, cause familial dementias. Although dementias due to APP/PSEN1/PSEN2 mutations are classified as familial Alzheimer disease (FAD) and those due to mutations in BRI2/ITM2B as British and Danish dementias (FBD, FDD), data suggest that these diseases have a common pathogenesis involving toxic APP metabolites. It was previously shown that FAD mutations in APP and PSENs promote activation of caspases leading to the hypothesis that aberrant caspase activation could participate in AD pathogenesis. Results: Here, we tested whether a similar mechanism applies to the Danish BRI2/ITM2B mutation. We have generated a genetically congruous mouse model of FDD, called FDDKI, which presents memory and synaptic plasticity deficits. We found that caspase-9 is activated in hippocampal synaptic fractions of FDDKI mice and inhibition of caspase-9 activity rescues both synaptic plasticity and memory deficits. Conclusion: These data directly implicate caspase-9 in the pathogenesis of Danish dementia and suggest that reducing caspase-9 activity is a valid therapeutic approach to treating human dementias

Inhibition of γ-secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia

Abstract Background A mutation in the BRI2/ITM2b gene causes familial Danish dementia (FDD). BRI2 is an inhibitor of amyloid-β precursor protein (APP) processing, which is genetically linked to Alzheimer’s disease (AD) pathogenesis. The FDD mutation leads to a loss of BRI2 protein and to increased APP processing. APP haplodeficiency and inhibition of APP cleavage by β-secretase rescue synaptic/memory deficits of a genetically congruous mouse model of FDD (FDDKI). β-cleavage of APP yields the β-carboxyl-terminal (β-CTF) and the amino-terminal-soluble APPβ (sAPPβ) fragments. γ-secretase processing of β-CTF generates Aβ, which is considered the main cause of AD. However, inhibiting Aβ production did not rescue the deficits of FDDKI mice, suggesting that sAPPβ/β-CTF, and not Aβ, are the toxic species causing memory loss. Results Here, we have further analyzed the effect of γ-secretase inhibition. We show that treatment with a γ-secretase inhibitor (GSI) results in a worsening of the memory deficits of FDDKI mice. This deleterious effect on memory correlates with increased levels of the β/α-CTFs APP fragments in synaptic fractions isolated from hippocampi of FDDKI mice, which is consistent with inhibition of γ-secretase activity. Conclusion This harmful effect of the GSI is in sharp contrast with a pathogenic role for Aβ, and suggests that the worsening of memory deficits may be due to accumulation of synaptic-toxic β/α-CTFs caused by GSI treatment. However, γ-secretase cleaves more than 40 proteins; thus, the noxious effect of GSI on memory may be dependent on inhibition of cleavage of one or more of these other γ-secretase substrates. These two possibilities do not need to be mutually exclusive. Our results are consistent with the outcome of a clinical trial with the GSI Semagacestat, which caused a worsening of cognition, and advise against targeting γ-secretase in the therapy of AD. Overall, the data also indicate that FDDKI is a valuable mouse model to study AD pathogenesis and predict the clinical outcome of therapeutic agents for AD.</p

Significance of Blood and Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease: Sensitivity, Specificity and Potential for Clinical Use

Alzheimer&rsquo;s disease (AD) is the most common type of dementia, affecting more than 5 million Americans, with steadily increasing mortality and incredible socio-economic burden. Not only have therapeutic efforts so far failed to reach significant efficacy, but the real pathogenesis of the disease is still obscure. The current theories are based on pathological findings of amyloid plaques and tau neurofibrillary tangles that accumulate in the brain parenchyma of affected patients. These findings have defined, together with the extensive neurodegeneration, the diagnostic criteria of the disease. The ability to detect changes in the levels of amyloid and tau in cerebrospinal fluid (CSF) first, and more recently in blood, has allowed us to use these biomarkers for the specific in-vivo diagnosis of AD in humans. Furthermore, other pathological elements of AD, such as the loss of neurons, inflammation and metabolic derangement, have translated to the definition of other CSF and blood biomarkers, which are not specific of the disease but, when combined with amyloid and tau, correlate with the progression from mild cognitive impairment to AD dementia, or identify patients who will develop AD pathology. In this review, we discuss the role of current and hypothetical biomarkers of Alzheimer&rsquo;s disease, their specificity, and the caveats of current high-sensitivity platforms for their peripheral detection

A Thr⁶⁶⁸Ala mutation on APP prevents the object recognition memory deficit of FDD_KI mice.

<p>(<b>a</b>) Western blot analysis of hippocampal synaptosomal preparations shown that the Thr to Ala mutation abolishes phosphorylation of Thr⁶⁶⁸ (APP^pThr⁶⁶⁸). Interestingly, only the mature form of APP (mAPP) and not the immature (imAPP), is found phosphorylated on this Thr in hippocampal synaptic fractions of WT mice. (<b>b</b> and <b>c</b>) Open field is a sensorimotor test for habituation, exploratory, emotional behavior, and anxiety-like behavior, in novel environments. The percent of time in the center (b) and the number of entries into the center (c) are indicators of anxiety levels. The more the mouse enters the center and explores it, the lower the level of anxiety-like behavior. Since the FDD_KI, FDD_KI/<i>APP^TA/TA</i>, FDD_KI/<i>APP^TA/WT</i>, <i>APP^TA/TA</i>, <i>APP^TA/WT</i> mice are similar to the WT animals there is no deficit or excess of anxiety. (<b>d</b>) All six genotypes (WT, FDD_KI, FDD_KI/<i>APP^TA/TA</i>, FDD_KI/<i>APP^TA/WT</i>, <i>APP^TA/TA</i>, <i>APP^TA/WT</i>) mice spent similar amounts of time exploring the two identical objects on day 1. (<b>e</b>) FDD_KI/APP^TA/TA and FDD_KI/APP^TA/WT mice behaved similarly to WT mice and prevented the deficit in the NOR tests found in FDD_KI mice at 6 months of age (FDD_KI versus FDD_KI/APP^TA/TA P = 0.011; FDD_KI versus FDD_KI/APP^TA/WT P = 0.0083; FDD_KI versus WT P<0.001), (<b>f)</b> 9 months of age (FDD_KI versus FDD_KI/APP^TA/TA P = 0.01; FDD_KI versus FDD_KI/APP^TA/WT P = 0.347; FDD_KI versus WT P = 0.000995), and (<b>g</b>) 12 months of age (FDD_KI versus FDD_KI/APP^TA/TA P = 0.0003; FDD_KI versus FDD_KI/APP^TA/WT P = 0.0002; FDD_KI versus WT P<0.0001). Thus the APP^TA point mutation prevented the novel object recognition deficit of FDD_KI mice.</p

A Thr⁶⁶⁸Ala mutation on APP prevents the synaptic deficits of FDD_KI mice.

<p>Normal LTP in FDD_KI/<i>APP^TA/TA</i> and <i>APP^TA/TA</i> compared with WT mice by two-way ANOVA (FDD_KI/<i>APP^TA/TA</i> versus WT mice: F(1,12) = 1.936; P = 0.187; <i>APP^TA/TA</i> versus WT F(1,12) = 0.989; P = 0.338). Two-way ANOVA shows impaired LTP in FDD_KI mice when compared with WT (F(1,13) = 15.125; P = 0.002), to FDD_KI/<i>APP^TA/TA</i> (F(1,13) = 12.759; P = 0.004) or to <i>APP^TA/TA</i> mice littermates (F(1,13) = 22.396; P<0.0001).</p