Henning Breyhan

Intraneuronal pyroglutamate-Abeta 3–42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model

It is well established that only a fraction of Aβ peptides in the brain of Alzheimer’s disease (AD) patients start with N-terminal aspartate (Aβ1D) which is generated by proteolytic processing of amyloid precursor protein (APP) by BACE. N-terminally truncated and pyroglutamate modified Aβ starting at position 3 and ending with amino acid 42 [Aβ3(pE)–42] have been previously shown to represent a major species in the brain of AD patients. When compared with Aβ1–42, 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 Aβ at N-terminal glutamate can be catalyzed in vitro. Here, we show that Aβ3(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 Aβ3–42 predominantly in hippocampus and cerebellum, few plaques were found in the cortex, cerebellum, brain stem and thalamus. The levels of converted Aβ3(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 Aβ3(pE)–42 is neurotoxic in vivo.

Sortilin-related receptor with A-type repeats (SORLA) affects the amyloid precursor protein-dependent stimulation of ERK signaling and adult neurogenesis.

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 β-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 pro-found 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.

Inflammatory changes are tightly associated with neurodegeneration in the brain and spinal cord of the APP/PS1KI mouse model of Alzheimer's disease

Inflammatory processes are considered to play an important role in the progression of neurodegenerative changes in Alzheimers disease (AD). In the present study, we performed a systematic expression analysis of various inflammatory and oxidative stress markers in pre-symptomatic and diseased APP/PS1KI mice. This mouse model has been previously shown to harbor severe pathological alterations, including behavioral deficits, axonal degeneration and hippocampal neuron loss starting at the age of 6 months. While the expression levels of most markers remained unchanged in 2-month-old APP/PS1KI mice, at the age of 6 months different astro- and microglia markers including GFAP, Cathepsin D, members of the Toll-like receptor (Tlr) family, TGFbeta-1 and osteopontin were up-regulated. In addition, oxidative stress markers, including the metallothioneins, were also significantly elevated at that time point. As expected, both brain and spinal cord were affected, the latter showing early activation of GFAP-positive astrocytes and Iba1-positive microglia in white matter fiber tracts, which might contribute to the previously reported axonal defects in this mouse model. These data add further evidence to the assumption that inflammatory processes are tightly associated with axonal degeneration and neuron loss, as is evident in the APP/PS1KI mouse model.

Deficits in working memory and motor performance in the APP/PS1ki mouse model for Alzheimer's disease

The APP/PS1ki mouse model for Alzheimers disease (AD) exhibits robust brain and spinal cord axonal degeneration and hippocampal CA1 neuron loss starting at 6 months of age. It expresses human mutant APP751 with the Swedish and London mutations together with two FAD-linked knocked-in mutations (PS1 M233T and PS1 L235P) in the murine PS1 gene. The present report covers a phenotypical analysis of this model using either behavioral tests for working memory and motor performance, as well as an analysis of weight development and body shape. At the age of 6 months, a dramatic, age-dependent change in all of these properties and characteristics was observed, accompanied by a significantly reduced ability to perform working memory and motor tasks. The APP/PS1ki mice were smaller and showed development of a thoracolumbar kyphosis, together with an incremental loss of body weight. While 2-month-old APP/PS1ki mice were inconspicuous in all of these tasks and properties, there is a massive age-related impairment in all tested behavioral paradigms. We have previously reported robust axonal degeneration in brain and spinal cord, as well as abundant hippocampal CA1 neuron loss starting at 6 months of age in the APP/PS1ki mouse model, which coincides with the onset of motor and memory deficits described in the present report.

Decreased plasma cholesterol levels during aging in transgenic mouse models of Alzheimer's disease.

A large number of studies deals with the association of cholesterol and Abeta levels, however, the results are so far controversial. Whereas some studies report on increased cholesterol levels, other authors refer to an association of decreased peripheral cholesterol and the incidence of Alzheimers disease. It is also questionable whether plasma cholesterol levels could be used as a predictive biomarker for the incidence of Alzheimers disease. In the present report, we studied the relationship between these two parameters during aging in different transgenic mouse models of Alzheimers disease, expressing both mutant human amyloid precursor protein and mutant human presenilin-1. Measurements of plasma cholesterol levels revealed a significant reduction in aged APP/PS1 and APP/PS1ki mice, whereas plasma levels in young and aged control mice remained almost unchanged. Furthermore, statistical analysis revealed a significant negative correlation between plasma cholesterol and brain Abeta42 levels during aging in the mice expressing both APP and PS1.

Intraneuronal β-Amyloid Is a Major Risk Factor – Novel Evidence from the APP/PS1KI Mouse Model

Accumulating evidence points to an important role of intraneuronal β-amyloid (Aβ) in the development of Alzheimer’s disease (AD), with its typical clinical symptoms like memory impairment and changes in personality. We have previously reported on the Aβ precursor protein and presenilin-1 knock-out (APP/PS1KI) mouse model with abundant intraneuronal Aβ42 accumulation and a 50% loss of CA1 neurons at 10 months of age. In addition, we observed reduced short- and long-term synaptic plasticity, hippocampal neuron loss, and reduced performance in a working memory task. These observations support a pivotal role of intraneuronal Aβ accumulation as a principal pathological trigger in AD.