It is well established that only a fraction of Ab peptides in the brain of Alzheimer's disease (AD) patients start with N-terminal aspartate (Ab 1D ) which is generated by proteolytic processing of amyloid precursor protein (APP) by BACE. N-terminally truncated and pyroglutamate modified Ab starting at position 3 and ending with amino acid 42 [Ab 3(pE)-42 ] have been previously shown to represent a major species in the brain of AD patients. When compared with Ab 1-42 , this peptide has stronger aggregation propensity and increased toxicity in vitro. Although it is unknown which peptidases remove the first two N-terminal amino acids, the cyclization of Ab at N-terminal glutamate can be catalyzed in vitro. Here, we show that Ab 3(pE)-42 induces neurodegeneration and concomitant neurological deficits in a novel mouse model (TBA2 transgenic mice). Although TBA2 transgenic mice exhibit a strong neuronal expression of Ab 3-42 predominantly in hippocampus and cerebellum, few plaques were found in the cortex, cerebellum, brain stem and thalamus. The levels of converted Ab 3(pE)-42 in TBA2 mice were comparable to the APP/PS1KI mouse model with robust neuron loss and associated behavioral deficits. Eight weeks after birth TBA2 mice developed massive neurological impairments together with abundant loss of Purkinje cells. Although the TBA2 model lacks important AD-typical neuropathological features like tangles and hippocampal degeneration, it clearly demonstrates that intraneuronal Ab 3(pE)-42 is neurotoxic in vivo.

Sortilin-related receptor with A-type repeats (SORLA) is a sorting receptor that impairs processing of amyloid precursor protein (APP) to soluble (s) APP and to the amyloid ␤-peptide in cultured neurons and is poorly expressed in patients with Alzheimer disease (AD). Here, we evaluated the consequences of Sorla gene defects on brain anatomy and function using mouse models of receptor deficiency. In line with a protective role for SORLA in APP metabolism, lack of the receptor results in increased amyloidogenic processing of endogenous APP and in aggravated plaque deposition when introduced into PDAPP mice expressing mutant human APP. Surprisingly, increased levels of sAPP caused by receptor deficiency correlate with profound stimulation of neuronal ERK signaling and with enhanced neurogenesis, providing in vivo support for neurotrophic functions of sAPP. Our data document a role for SORLA not only in control of plaque burden but also in APP-dependent neuronal signaling and suggest a molecular explanation for increased neurogenesis observed in some AD patients.Sortilin-related receptor with A-type repeats (SORLA), 4 also known as LR11 or SORL1 is a sorting receptor that controls intracellular transport and processing of the amyloid precursor protein (APP) in cultured neurons (1-4). The receptor shuttles between Golgi, plasma membrane, and endosomes (5), and determines residence time of the precursor protein in the various intracellular compartments (3). Most importantly, the receptor promotes retention of APP in subcellular compartments less favorable for processing and thereby reduces the extent of proteolytic breakdown into both amyloidogenic and non-amyloidogenic products. Consistent with its protective role in APP catabolism, increasing SORLA expression in cells reduces conversion of APP to the amyloid ␤-peptide (A␤) and soluble (s) APP fragments, while low levels of receptor activity accelerate generation of these processing products (3,4,6).Recently, a possible role for SORLA as a risk factor for sporadic Alzheimer disease (AD) was supported by the association of inherited gene variants with the occurrence of this disease in several populations (7,8). These findings support earlier studies that reported low levels of Sorla gene expression in patients suffering from sporadic AD, but not in individuals with familial forms of the disease that are caused by defects in genes encoding APP or presenilin 1 and 2 (9, 10).A substantial amount of data correlate SORLA activity with APP processing and A␤ production rates in cell cultures. Still, the normal physiological role of SORLA-dependent regulation of APP processing in vivo and the pathophysiological consequences of insufficient receptor activity in the brain remain poorly understood.Here, we used alternative mouse models with targeted Sorla gene disruption to address the molecular and pathophysiological consequences of impaired SORLA activity for neuronal function and AD pathology in vivo. Our findings identified a distinct increase in A␤ production and amyloid pl...

No abstract

Abeta accumulation has an important function in the etiology of Alzheimer's disease (AD) with its typical clinical symptoms, like memory impairment and changes in personality. However, the mode of this toxic activity is still a matter of scientific debate. We used the APP/PS1KI mouse model for AD, because it is the only model so far which develops 50% hippocampal CA1 neuron loss at the age of 1 year. Previously, we have shown that this model develops severe learning deficits occurring much earlier at the age of 6 months. This observation prompted us to study the anatomical and cellular basis at this time point in more detail. In the current report, we observed that at 6 months of age there is already a 33% CA1 neuron loss and an 18% atrophy of the hippocampus, together with a drastic reduction of long-term potentiation and disrupted paired pulse facilitation. Interestingly, at 4 months of age, there was no long-term potentiation deficit in CA1. This was accompanied by reduced levels of pre-and post-synaptic markers. We also observed that intraneuronal and total amount of different Abeta peptides including N-modified, fibrillar and oligomeric Abeta species increased and coincided well with CA1 neuron loss. Overall, these data provide the basis for the observed robust working memory deficits in this mouse model for AD at 6 months of age.

No abstract