Intraneuronal Aβ Causes the Onset of Early Alzheimer’s Disease-Related Cognitive Deficits in Transgenic Mice

Abstract

Progressive memory loss and cognitive dysfunction are the hallmark clinical features of Alzheimer's disease (AD). Identifying the molecular triggers for the onset of AD-related cognitive decline presently requires the use of suitable animal models, such as the 3xTg-AD mice, which develop both amyloid and tangle pathology. Here, we characterize the onset of learning and memory deficits in this model. We report that 2-month-old, prepathologic mice are cognitively unimpaired. The earliest cognitive impairment manifests at 4 months as a deficit in long-term retention and correlates with the accumulation of intraneuronal Abeta in the hippocampus and amygdala. Plaque or tangle pathology is not apparent at this age, suggesting that they contribute to cognitive dysfunction at later time points. Clearance of the intraneuronal Abeta pathology by immunotherapy rescues the early cognitive deficits on a hippocampal-dependent task. Reemergence of the Abeta pathology again leads to cognitive deficits. This study strongly implicates intraneuronal Abeta in the onset of cognitive dysfunction.

Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein‐specific antibodies

“…This coincides with cognitive impairment at 4 months as a deficit in long‐term retention and correlates with the accumulation of intraneuronal Aβ in the CA1 region of hippocampus and amygdala (Billings et al ., 2005). At around 6 months, extracellular amyloid plaques become apparent in layers IV and V of the neocortex and later on as well in the CA1 region of the hippocampus of 3xTg mice which coincides with a decreased LTP and impaired synaptic transmission to age matched wild‐type littermates (Oddo et al ., 2003; Billings et al ., 2005). This spatiotemporal course of Aβ deposition correlates well with the transgene expression pattern of hAPP observed with the antibody 1D1 which strongly labelled pyramidal neurons in layer V and CA1 of the hippocampus, while CA2 and CA3 are almost devoid of APP transgene expressing neurons (Fig.…”

Age-related accumulation of Reelin in amyloid-like deposits

“…These transgenic mice are characterized by early intraneuronal accumulation of Aβ, deficits in LTP and learning and memory before the formation of fibrillary plaques and tangles (Billings et al, 2005;Oddo et al, 2003). Immunotherapy results in clearance of intracellular Aβ and improvement in cognitive performance (Billings et al, 2005;Oddo et al, 2004), implicating soluble/intraneuronal rather than fibrillary Aβ as causative factors of cognitive impairments. Although cognitive deficits persist or worsen, intraneuronal Aβ is relatively transient and declines with disease progression in humans and animal AD models (Wirths et al, 2004).…”

Nanoscopic Characterisation of Individual Endogenous Protein Aggregates in Human Neuronal Cells

“…Soluble nanometre‐sized protein oligomers have been identified as the major cytotoxic species in AD and PD,7, 8, 9, 10 but the study of such species has remained challenging, as they tend to be low in abundance and adopt a wide range of heterogeneous structures. To overcome this problem, we have developed an array of single‐molecule techniques11, 12, 13, 14 to observe oligomeric species individually, and have applied them to characterise the aggregation pathway of several disease‐related proteins in vitro.…”