N-truncated amyloid β (Aβ) 4-42 forms stable aggregates and induces acute and long-lasting behavioral deficits

Abstract

N-truncated Aβ4-42 is highly abundant in Alzheimer disease (AD) brain and was the first Aβ peptide discovered in AD plaques. However, a possible role in AD aetiology has largely been neglected. In the present report, we demonstrate that Aβ4-42 rapidly forms aggregates possessing a high aggregation propensity in terms of monomer consumption and oligomer formation. Short-term treatment of primary cortical neurons indicated that Aβ4-42 is as toxic as pyroglutamate Aβ3-42 and Aβ1-42. In line with these findings, treatment of wildtype mice using intraventricular Aβ injection induced significant working memory deficits with Aβ4-42, pyroglutamate Aβ3-42 and Aβ1-42. Transgenic mice expressing Aβ4-42 (Tg4-42 transgenic line) developed a massive CA1 pyramidal neuron loss in the hippocampus. The hippocampus-specific expression of Aβ4-42 correlates well with age-dependent spatial reference memory deficits assessed by the Morris water maze test. Our findings indicate that N-truncated Aβ4-42 triggers acute and long-lasting behavioral deficits comparable to AD typical memory dysfunction.

Endothelial LRP1 transports amyloid-β1–42 across the blood-brain barrier

“…Next, we investigated how brain endothelial LRP1 deficiency affects AD-related behavior by examining spatial learning and memory (40,41). We used three different tests to examine motor deficits, string suspension, inverted grip, and balance beam, and found that no mice in any tested group showed abnormalities (Supplemental Figure 6).…”

Phosphorylation Interferes with Maturation of Amyloid-β Fibrillar Structure in the N Terminus

“…The N-terminal region of A␤ is host for a wide range of events such as phosphorylation (23), metal binding (28,42), tyrosine nitration (43), and truncation (19,20). These events may modulate the role of A␤ in oxidative damage (44) and induction of inflammation (45) and alter the efficiency of prionlike self-propagation (24) and their interaction with biological targets such as cellular lipid membranes (46).…”

“…Despite the fact that the N-terminal region of A␤ is mainly unstructured in these fibrillar models, several lines of evidence point to an important role of this region in pathogenic aggregation. In particular, it has been shown that toxic A␤ assembly is enhanced by mutations in this region (A2V, H6R, or D7N) (17,18) as well as N-terminal truncation with or without pyroglutamate formation (19,20). Furthermore, antibodies against the N-terminal region inhibit A␤ amyloid formation (21), and the conformational propensity of the N-terminal region controls the partitioning between A␤ oligomers and protofibrils (22).…”

Altered neurogenesis in mouse models of Alzheimer disease

“…Surprisingly, no beneficial effects on working memory, extracellular Ab plaque load, neuron loss, as well as hippocampal neurogenesis could be detected. 25 A direct link between intraneuronal Ab accumulation and subsequent neuron loss in distinct brain regions has been also established in mouse models like TBA2.1 34 or Tg4-42, 35 engineered to directly overexpress mutant Ab peptides in the absence of mutant APP overexpression. These models use the neuronspecific Thy1-promotor to overexpress the N-terminal truncated Ab species Ab3-42 or Ab4-42 and are characterized by extensive CA1 neuron loss and associated behavioral deficits.…”

“…These models use the neuronspecific Thy1-promotor to overexpress the N-terminal truncated Ab species Ab3-42 or Ab4-42 and are characterized by extensive CA1 neuron loss and associated behavioral deficits. [34][35][36] In the Tg4-42 model, enhanced physical activity using enriched housing in cages equipped with running wheels resulted in an amelioration of CA1 neuron loss, accompanied by a significantly increased overall dentate gyrus granule cell number and a concomitant increase in the number of DCX-positive cells in the DG. 26 So far, no accumulation of Ab peptides within dentate gyrus neurons has been reported in any of the mouse models that have been studied.…”