. Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein E depends on isoform, aging, and overexpression of amyloid beta peptides but not on plaque formation. J Neurosci. 2002 Dec 15;22(24):10539-48. PubMed.

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  1. This study by L. Mucke and co-workers deserves credit for analyzing the "ApoE-isoform effect" in AD, a problem that is far from understood at the physiological level. The interesting results are situated on two levels:(i)synaptic deficit is evident in non-plaque bearing APP mice and (ii)ApoE3 but not ApoE4 delays the age- and Aß-dependent synaptic deficits. The early synaptic deficits are indeed independent of plaque formation, since they are evident in the form of decreased LTP and defective cognition (water-maze and object recogition) in APP-mice long before plaques form (Moechars et al., 1999) and in mice that lack neuronal PS1 (Dewachter et al., 2002). This is likely due to defective calcium-homeostasis (Herms et al., 2003). That "AD is a synaptic disease" has thereby been demonstrated, at least in the mouse models that we have generated over the years. A note of caution to the second conclusion is in place: the mice express the human ApoE isoforms in neurons as driven by the neuron-specific enolase gene promoter. Neuronal expression of ApoE, as originally hypothesised by Alan Roses, does affect neuronal functions and integrity by intefering with tau and micro-tubular transport (Tesseur et al., 2000; 2000). It is evident and even likely that this would affect synaptic functioning and confound the observations, which need therefore further analysis to confirm their importance.

    References:

    . Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J Biol Chem. 1999 Mar 5;274(10):6483-92. PubMed.

    . Neuronal deficiency of presenilin 1 inhibits amyloid plaque formation and corrects hippocampal long-term potentiation but not a cognitive defect of amyloid precursor protein [V717I] transgenic mice. J Neurosci. 2002 May 1;22(9):3445-53. PubMed.

    . Capacitive calcium entry is directly attenuated by mutant presenilin-1, independent of the expression of the amyloid precursor protein. J Biol Chem. 2003 Jan 24;278(4):2484-9. PubMed.

    . Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice. Am J Pathol. 2000 Mar;156(3):951-64. PubMed.

    . Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord. Am J Pathol. 2000 Nov;157(5):1495-510. PubMed.