. 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, JBC, 1999, 274:6483-6492) and in mice that lack neuronal PS1 (Dewachter et al, J Neurosci., 2002, 22:3445-53). This is likely due to defective calcium-homeostasis (Herms et al, JBC, 2003, 275: 2484-2489). 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, Am J Pathol.,2000,156:951-964 and 157:1495-1510). 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.