Neural oscillations during cognitive processes in an App 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 ß 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 AppNL-G-Fmodel, 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 Aß1-42 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 AppNL-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 AppNL-G-F mice, we did observe subtle changes in PAC in the wild-type mice that were not present in the AppNL-G-F mice.

Young to Middle-Aged Dogs with High Amyloid-ß Levels in Cerebrospinal Fluid are Impaired on Learning in Standard Cognition tests.

Understanding differences in Alzheimer's disease biomarkers before the pathology becomes evident can contribute to an improved understanding of disease pathogenesis and treatment. A decrease in amyloid-ß (Aß)42 in cerebrospinal fluid (CSF) is suggested to be a biomarker for Aß deposition in brain. However, the relevance of CSF Aß levels prior to deposition is not entirely known. Dogs are similar to man with respect to amyloid-ß protein precursor (AßPP)-processing, age-related amyloid plaque deposition, and cognitive dysfunction. In the current study, we evaluated the relation between CSF Aß42 levels and cognitive performance in young to middle-aged dogs (1.5-7 years old). Additionally, CSF sAßPPα and sAßPPß were measured to evaluate AßPP processing, and CSF cytokines were measured to determine the immune status of the brain. We identified two groups of dogs showing consistently low or high CSF Aß42 levels. Based on prior studies, it was assumed that at this age no cerebral amyloid plaques were likely to be present. The cognitive performance was evaluated in standard cognition tests. Low or high Aß concentrations coincided with low or high sAßPPα, sAßPPß, and CXCL-1 levels, respectively. Dogs with high Aß concentrations showed significant learning impairments on delayed non-match to position (DNMP), object discrimination, and reversal learning compared to dogs with low Aß concentrations. Our data support the hypothesis that high levels of CSF Aß in dogs coincide with lower cognitive performance prior to amyloid deposition. Further experiments are needed to investigate this link, as well as the relevance with respect to Alzheimer's disease pathology progression.

Current insights into molecular mechanisms of Alzheimer disease and their implications for therapeutic approaches.

During the last 10 years, a lot of progress has been made in unraveling the pathogenic cascade leading to Alzheimer disease (AD). According to the most widely accepted hypothesis, production and aggregation of the amyloid beta (Abeta) peptide plays a key role in AD, and thus therapeutic interference with these processes is the subject of intense research. However, some important aspects of the disease mechanism are not yet fully understood. There is no consensus as yet on whether the disease acts through a loss- (LOF) or a gain-of-function (GOF) mechanism. While for many years, an increased production of Abeta42 was considered to be the prime culprit for the initiation of the disease process, and accordingly Abeta42 is elevated by AD-related presenilin(PS) mutations, recent data strongly suggest that PS mutations also lead to a LOF of PS towards a plethora of its substrates including amyloid precursor protein. How this PS LOF, especially decreased Abeta40 secretion due to mutant PS, impacts on the disease pathogenesis is yet to be elucidated. Secondly, vascular abnormalities--frequently observed to co-occur with AD--might also play a critical role in the initiation and aggravation of AD pathology given that the elimination of Abeta through a vascular route is an important brain Abeta clearance mechanism and its failure leads to formation of vascular amyloidosis and dense-core plaques. In this review, we will first focus on the important issue of a LOF versus a GOF mechanism for AD due to mutant PS, as well as on the possible role of vascular damage and reduced perfusion in AD. Special emphasis will be given to some of the AD mouse models that have helped to gain insights into the disease mechanism. Secondly, considering these mechanistic insights, we will discuss some therapeutic strategies which are currently in clinical or preclinical trials for AD.