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Buttini M, Yu GQ, Shockley K, Huang Y, Jones B, Masliah E, Mallory M, Yeo T, Longo FM, Mucke L. 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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KULeuven
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:
Moechars D, Dewachter I, Lorent K, Reversé D, Baekelandt V, Naidu A, Tesseur I, Spittaels K, Haute CV, Checler F, Godaux E, Cordell B, Van Leuven F. 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.
Dewachter I, Reversé D, Caluwaerts N, Ris L, Kuipéri C, Van den Haute C, Spittaels K, Umans L, Serneels L, Thiry E, Moechars D, Mercken M, Godaux E, Van Leuven F. 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.
Herms J, Schneider I, Dewachter I, Caluwaerts N, Kretzschmar H, Van Leuven F. 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.
Tesseur I, Van Dorpe J, Spittaels K, Van den Haute C, Moechars D, Van Leuven F. 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.
Tesseur I, Van Dorpe J, Bruynseels K, Bronfman F, Sciot R, Van Lommel A, Van Leuven F. 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.
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