Herpes Simplex Virus 1 (HSV-1)-Based Vectors - Viral Vector Approaches in Neurobiology and Brain Diseases - page 70

amyloid and tau pathological progression were signifi cantly more
important in [HSV(IE)A (CMV)IL-4]-vaccinated mice than in

control experimental groups, underlining the potential of amplicons
for A

β

-immune-therapy of AD [ 134 ].
The microtubule-associated protein tau (MAPT) and alpha-
synuclein (SNCA) genes play central roles in neurodegenerative
disorders. Peruzzi and colleagues recently generated amplicon vec-
tors carrying either the 143-kb MAPT or the 135-kb SNCA locus.
They have used these vectors to study regulation of gene expres-
sion of both, MAPT and SNCA transgenes, and have demonstrated
functional complementation in cultured neurons and organotypic
brain slices. They showed that cultured neurons transduced with
either amplicon vector expressed the human loci similar to the
endogenous gene. In particular, multiple MAPT transcripts were
expressed under strict developmental and cell type-specifi c control.
Primary cultures from Mapt −/− embryos had been shown to be resis-
tant to A

β

peptide-induced toxicity suggesting that the tau protein
may mediate the neurotoxicity of A

β

fi brils. To test the functionality
of the MAPT transgene, the authors examined whether it could
restore the responsiveness to A

β

peptide in the Mapt −/− neurons
and organotypic brain slices. In both preparations from Mapt(−/−)
mice, the MAPT vector expressed the tau protein, as detected by
ELISA and immune-cytochemistry and restored sensitivity of
Mapt(−/−) neurons to A

β

peptide treatment [ 135 ]. As stated by the
authors, the faithful retention of gene expression and phenotypic
complementation by this system provides a novel and powerful
approach to analyze neurological disease genes.
Some neurodegenerative pathologies, such as AD or
Parkinson's disease (PD), as well as some forms of depression, have
been associated to dysfunction of receptor-neurotransmitter systems.
L -glutamate is the major excitatory neurotransmitter in the CNS.
For this reason, glutamate receptors represent an attractive molec-
ular target in the treatment of these neurodegenerative diseases
and also in epilepsy, schizophrenia, and ischemia. There is recent
evidence that the transmembrane protein APP appears capable of
interacting with N-Methyl- D -Aspartate Receptors (NMDAR)
[ 136 , 137 ]. These ionotropic glutamate receptors are tetramers
made of two NR1 subunits and different NR2 (A-D), and/or
NR3 (A-B) subunits, with NR1 being essential for receptor assem-
bly [ 138 ]. Nowadays, association of NMDAR with several neuro-
pathologies has been continuously growing up. Thus, the
generation of novel tools that modify expression and structure of
NMDARs should help us to understand both the normal function-
ing and the physiopathology of these receptors. It was proposed
that ADDLs bind to NMDAR or to postsynaptic complexes con-
taining it, acting as gain of function ligands [ 125 , 126 , 139 ]. By
targeting such postsynaptic complexes, ADDLs would activate a
cascade of signals that lead to an increase in intracellular reactive

β