Neural oscillations during cognitive processes in an <i>App</i> knock-in mouse model of Alzheimer's disease pathology

Multiple animal models have been created to gain insight into Alzheimer's disease (AD) pathology. Among the most commonly used models are transgenic mice overexpressing human amyloid precursor protein (APP) with mutations linked to familial AD, resulting in the formation of amyloid beta plaques, one of the pathological hallmarks observed in AD patients. However, recent evidence suggests that the overexpression of APP by itself can confound some of the reported observations. Therefore, we investigated in the present study the App(NL-G-F)model, an App knock-in (App-KI) mouse model that develops amyloidosis in the absence of APP-overexpression. Our findings at the behavioral, electrophysiological, and histopathological level confirmed an age-dependent increase in A beta 1-42 levels and plaque deposition in these mice in accordance with previous reports. This had apparently no consequences on cognitive performance in a visual discrimination (VD) task, which was largely unaffected in App(NL-G-F) mice at the ages tested. Additionally, we investigated neurophysiological functioning of several brain areas by phase-amplitude coupling (PAC) analysis, a measure associated with adequate cognitive functioning, during the VD task (starting at 4.5 months) and the exploration of home environment (at 5 and 8 months of age). While we did not detect age-dependent changes in PAC during home environment exploration for both the wild-type and the App(NL-G-F) mice, we did observe subtle changes in PAC in the wild-type mice that were not present in the App(NL-G-F) mice

Anti-tau intrabodies: From anti-tau immunoglobulins to the development of functional scFv intrabodies

Over the last decade, there has been a growing interest in intrabodies and their therapeutic potential. Intrabodies are antibody fragments that are expressed inside a cell to target intracellular antigens. In the context of intracellular protein misfolding and aggregation, such as tau pathology in Alzheimer’s disease, intrabodies have become an interesting approach as there is the possibility to target early stages of aggregation. As such, we engineered three anti-tau monoclonal antibodies into single-chain variable fragments for cytoplasmic expression and activity: PT51, PT77, and hTau21. Due to the reducing environment of the cytoplasm, single-chain variable fragment (scFv) aggregation is commonly observed. Therefore, we also performed complementarity-determining region (CDR) grafting into three different stable frameworks to rescue solubility and intracellular binding. All three scFvs retained binding to tau after cytoplasmic expression in HEK293 cells, in at least one of the frameworks. Subsequently, we show their capacity to interfere with either mouse or mutant human tau aggregation in two different primary mouse neuron models and organotypic hippocampal slice cultures. Collectively, our work extends the current knowledge on intracellular tau targeting with intrabodies, providing three scFv intrabodies that can be used as immunological tools to target tau inside cells

Diagnostic Accuracy of Cerebrospinal Fluid Amyloid-beta Isoforms for Early and Differential Dementia Diagnosis

Background: Overlapping cerebrospinal fluid biomarkers (CSF) levels between Alzheimer's disease (AD) and non-AD patients decrease differential diagnostic accuracy of the AD core CSF biomarkers. Amyloid-beta (A beta) isoforms might improve the AD versus non-AD differential diagnosis. Objective: To determine the added diagnostic value of A beta isoforms, A beta(1-37), A beta(1-38), and A beta(1-40), as compared to the AD CSF biomarkers A beta(1-42), T-tau, and P-tau(181P). Methods: CSF from patients with dementia due to AD (n = 50), non-AD dementias (n = 50), mild cognitive impairment due to AD(n = 50) and non-demented controls (n = 50) was analyzed with a prototype multiplex assay using MSD detection technology. The non-AD group consisted of frontotemporal dementia (FTD; n = 17), dementia with Lewy bodies (DLB; n = 17), and vascular dementia (n = 16). Results: A beta(1-37) and A beta(1-38) increased accuracy to differentiate AD from FTD or DLB. A beta(1-37), A beta(1-38), and A beta(1-40) levels correlated with Mini-Mental State Examination scores and disease duration in dementia due to AD. The A beta(1-42)/A beta(1-40) ratio improved diagnostic performance of A beta(1-42) in most differential diagnostic situations. A beta(1-42) levels were lower in APOE epsilon 4 carriers compared to non-carriers. Conclusions: A beta isoforms help to differentiate AD from FTD and DLB. A beta isoforms increase diagnostic performance of A beta(1-42). In contrast to A beta(1-42), A beta isoforms seem to be correlated with disease severity in AD. Adding the A beta isoforms to the current biomarker panel could enhance diagnostic accuracy