The Uppsala APP deletion causes early onset autosomal dominant Alzheimer's disease by altering APP processing and increasing amyloid β fibril formation

Point mutations in the amyloid precursor protein gene (APP) cause familial Alzheimer's disease (AD) by increasing generation or altering conformation of amyloid beta (A beta). Here, we describe the Uppsala APP mutation (Delta 690-695), the first reported deletion causing autosomal dominant AD. Affected individuals have an age at symptom onset in their early forties and suffer from a rapidly progressing disease course. Symptoms and biomarkers are typical of AD, with the exception of normal cerebrospinal fluid (CSF) A beta 42 and only slightly pathological amyloid-positron emission tomography signals. Mass spectrometry and Western blot analyses of patient CSF and media from experimental cell cultures indicate that the Uppsala APP mutation alters APP processing by increasing beta-secretase cleavage and affecting alpha-secretase cleavage. Furthermore, in vitro aggregation studies and analyses of patient brain tissue samples indicate that the longer form of mutated A beta, A beta Upp1-42(Delta 19-24), accelerates the formation of fibrils with unique polymorphs and their deposition into amyloid plaques in the affected brain

Andersson G: Internet-delivered attention bias modification training in individuals with social anxiety disorder - a double blind randomized controlled trial

R E S E A R C H A R T I C L E Open Access Internet-delivered attention bias modification training in individuals with social anxiety disorder -a double blind randomized controlled trial Abstract Background: Computerized cognitive bias modification for social anxiety disorder has in several well conducted trials shown great promise with as many as 72% no longer fulfilling diagnostic criteria after a 4 week training program. To test if the same program can be transferred from a clinical setting to an internet delivered home based treatment the authors conducted a randomized, double-blind placebo-controlled trial. Methods: After a diagnostic interview 79 participants were randomized to one of two attention training programs using a probe detection task. In the active condition the participant was trained to direct attention away from threat, whereas in the placebo condition the probe appeared with equal frequency in the position of the threatening and neutral faces

Transferrin Receptor Binding BBB-Shuttle Facilitates Brain Delivery of Anti-A beta-Affibodies

Affibodies targeting amyloid-beta (A beta) could potentially be used as therapeutic and diagnostic agents in Alzheimer's disease (AD). Affibodies display suitable characteristics for imaging applications such as high stability and a short biological half-life. The aim of this study was to explore brain delivery and retention of A beta protofibril-targeted affibodies in wild-type (WT) and AD transgenic mice and to evaluate their potential as imaging agents. Two affibodies, Z5 and Z1, were fused with the blood-brain barrier (BBB) shuttle single-chain variable fragment scFv8D3. In vitro binding of I-125-labeled affibodies with and without scFv8D3 was evaluated by ELISA and autoradiography. Brain uptake and retention of the affibodies at 2 h and 24 h post injection was studied ex vivo in WT and transgenic (tg-Swe and tg-ArcSwe) mice. At 2 h post injection, [I-125]I-Z5 and [I-125]I-Z1 displayed brain concentrations of 0.37 +/- 0.09% and 0.46 +/- 0.08% ID/g brain, respectively. [I-125]I-scFv8D3-Z5 and [I-125]I-scFv8D3-Z1 showed increased brain concentrations of 0.53 +/- 0.16% and 1.20 +/- 0.35%ID/g brain. At 24 h post injection, brain retention of [I-125]I-Z1 and [I-125]I-Z5 was low, while [I-125]I-scFv8D3-Z1 and [I-125]I-scFv8D3-Z5 showed moderate brain retention, with a tendency towards higher retention of [I-125]I-scFv8D3-Z5 in AD transgenic mice. Nuclear track emulsion autoradiography showed greater parenchymal distribution of [I-125]I-scFv8D3-Z5 and [I-125]I-scFv8D3-Z1 compared with the affibodies without scFv8D3, but could not confirm specific affibody accumulation around A beta deposits. Affibody-scFv8D3 fusions displayed increased brain and parenchymal delivery compared with the non-fused affibodies. However, fast brain washout and a suboptimal balance between A beta and mTfR1 affinity resulted in low intrabrain retention around A beta deposits

The Uppsala APP deletion causes early onset autosomal dominant Alzheimer’s disease by altering APP processing and increasing amyloid β fibril formation

Point mutations in the amyloid precursor protein gene (APP) cause familial Alzheimer’s disease (AD) by increasing generation or altering conformation of amyloid β (Aβ). Here, we describe the Uppsala APP mutation (Δ690–695), the first reported deletion causing autosomal dominant AD. Affected individuals have an age at symptom onset in their early forties and suffer from a rapidly progressing disease course. Symptoms and biomarkers are typical of sporadic AD, except that these three patients had high cerebrospinal fluid (CSF) Aβ42 and only modest brain pathology as detected by amyloid-positron emission tomography. Mass spectrometry and Western blot analyses of patient CSF and media from experimental cell cultures indicate that the Uppsala APP mutation alters APP processing by increasing β-secretase cleavage and affecting α-secretase cleavage. Furthermore, in vitro aggregation studies and analyses of patient brain tissue samples indicate that the longer form of mutated Aβ, AβUpp1–42Δ19–24, accelerates the formation of fibrils with unique polymorphs and their deposition into amyloid plaques in the affected brain

Internet-delivered attention bias modification training in individuals with social anxiety disorder : a double blind randomized controlled trial

Background: Computerized cognitive bias modification for social anxiety disorder has in several well conducted trials shown great promise with as many as 72% no longer fulfilling diagnostic criteria after a 4 week training program. To test if the same program can be transferred from a clinical setting to an internet delivered home based treatment the authors conducted a randomized, double-blind placebo-controlled trial. Methods: After a diagnostic interview 79 participants were randomized to one of two attention training programs using a probe detection task. In the active condition the participant was trained to direct attention away from threat, whereas in the placebo condition the probe appeared with equal frequency in the position of the threatening and neutral faces. Results: Results were analyzed on an intention-to-treat basis, including all randomized participants. Immediate and 4-month follow-up results revealed a significant time effect on all measured dimensions (social anxiety scales, general anxiety and depression levels, quality of life). However, there were no time x group interactions. The lack of differences in the two groups was also mirrored by the infinitesimal between group effect size both at post test and at 4-month follow-up. Conclusion: We conclude that computerized attention bias modification may need to be altered before dissemination for the Internet. Trial registration: ISRCTN0171512