Absence of C1q Leads to Less Neuropathology in Transgenic Mouse Models of Alzheimer's Disease

Abstract

C1q, the recognition component of the classical complement activation pathway, is a multifunctional protein known to be expressed in brain of Alzheimer's disease (AD) patients. To experimentally address the role of C1q in AD, a mouse model lacking C1q (APPQϪ/Ϫ) was generated by crossing Tg2576 animals (APP) with C1q-deficient mice. The pathology of APPQϪ/Ϫ was compared with that of APP mice and B6SJL controls at 3-16 months of age by immunohistochemistry and Western blot analysis. At younger ages (3-6 months), when no plaque pathology was present, no significant differences were seen in any of the neuronal or glial markers tested. At older ages (9 -16 months), the APP and APPQϪ/Ϫ mice developed comparable total amyloid and fibrillar ␤-amyloid in frontal cortex and hippocampus; however, the level of activated glia surrounding the plaques was significantly lower in the APPQϪ/Ϫ mice at 12 and 16 months. In addition, although Tg2576 mice showed a progressive decrease in synaptophysin and MAP2 in the CA3 area of hippocampus compared with control B6SJL at 9, 12, and 16 months, the APPQϪ/Ϫ mice had significantly less of a decrease in these markers at 12 and 16 months. In a second murine model for AD containing transgenes for both APP and mutant presenilin 1 (APP/PS1), a similar reduction of pathology was seen in the APPPS1QϪ/Ϫ mice. These data suggest that at ages when the fibrillar plaque pathology is present, C1q exerts a detrimental effect on neuronal integrity, most likely through the activation of the classical complement cascade and the enhancement of inflammation.

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

“…Consistent with a previous report showing decreased MAP2 immunoreactivity in the hippocampus of APP/PS1 mice (Fonseca et al, 2004), our semiquantitative results showed that the vehicle-treated APP/PS1 mice had a dramatic decrease (50%) in MAP2 reactivity in the pyramidal neurons of the CA1 region of the hippocampus compared with the vehicle-treated wild-type controls (Fig. 6 A, B).…”

“…Neuronal degeneration and loss observed in the brains of AD patients (West et al, 1994) and in the brains of APP/PS1 transgenic mice (Fonseca et al, 2004;Rutten et al, 2005) is hypothesized to be exacerbated by an inflammatory reaction (McGeer and McGeer, 1999). Given the inhibitory effect of ATRA on glial activation, an indicator of CNS inflammation, we determined the effect of ATRA on neuronal integrity.…”

Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons

“…C1q components have also previously been suggested to be produced by injured or stressed neurons, especially in Alzheimer's disease (36)(37)(38)(39)(40). Furthermore, deletion of C1q has been shown to reduce pathological signs in APP-transgenic Alzheimer-mice (41). In light of the recent finding that a proportion of mutant SOD1 may be secreted (42), as well as liberated by cell death, and therefore could act from outside the motor neurons, it is tempting to speculate that the induced complement system might recognize such extracellular, misfolded mutant SOD1 and mark the motor neuron for attack by immune cells.…”

Phenylbutyrate Ameliorates Cognitive Deficit and Reduces Tau Pathology in an Alzheimer's Disease Mouse Model

“…Postsynaptic deficits of PSD95, GluR1, and MAP-2 described in brains from AD patients and Tg2576 mice (Almeida et al, 2005;Fonseca et al, 2004;Liu et al, 2005) may contribute to synaptic dysfunction with resultant impaired learning. In agreement with that, we observed reduced expression of AMPA receptor subunit GluR1, PSD95, and MAP-2 in Tg2576 hippocampus that may contribute to poor performance in the water maze.…”