Gene Delivery and Gene Therapy for Alzheimer’s Disease - Gene Delivery and Therapy for Neurological Disorders - page 97

The RAWM measures the ability of a mouse or rat to remember the
location of a hidden underwater platform in repeated trials. Double
transgenic APP/PS1 mice show spatial memory defi cit as mea-
sured by this test [ 84 - 86 ]. Changes in function at the synaptic
level can also be measured by electrophysiology. Young PDAPP
(J20) and PDAPP (J9) mice, which contain human APP carrying
familial AD Swedish (K670N/M671L) and Indiana (V717F)
mutations, show a defi cit in hippocampal basal synaptic transmis-
sion prior to the formation of A plaques, as measured by change

in excitatory postsynaptic potential (EPSP) slope [ 87 ]. Similarly,
Chapman et al. showed that aged APP Swe mice display normal fast
synaptic transmission and short-term plasticity, but are impaired in
long-term potentiation (LTP) in CA1 and the dentate gyrus [ 88 ].
Prominent hippocampal neuronal loss is seen in AD patients, espe-
cially in CA1 [ 82 ]; thus, measures of synaptic transmission in this
region may reveal the effi cacy of a certain treatment for AD. Basal
synaptic transmission, LTP, and long-term depression (LTD) are
common electrophysiological measures of synaptic function and
plasticity that can easily be applied to AD studies using AAV gene
therapy.
Although widespread neuronal loss is seen in AD, it is believed
to be a disease of synaptic failure. This synaptic failure, thought to
be caused by the toxicity of amyloid plaques and neurofi brillary
tangles, correlates with cognitive decline and is believed to be the
initial cause of memory impairment prior to neuron loss [ 89 ]. This
is supported by electrophysiological studies as outlined previously
[ 87 , 88 ] as well as by studies of synapse density and expression of
synaptic markers. Whereas A

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load and neuron death do not cor-
relate with cognitive decline [ 90 ], loss of the presynaptic vesicle
protein synaptophysin seen in AD patients in the hippocampus
[ 83 ] and prefrontal cortex [ 90 ] correlates with cognitive decline.
Histological examination of the brain readily reveals changes in
synapse morphology and density that correlate with cognitive
decline in AD. Synapse density can be measured by immunohisto-
chemistry using antibodies against synaptophysin or other synaptic
proteins. Hsia et al. used this method to show that PDAPP (J9)
mice show signifi cantly decreased synaptophysin-positive terminals
in the CA1 region of the hippocampus at as early as 2-3 months of
age [ 87 ]. Neuronal loss can also be measured with neuronal mark-
ers such as microtubule-associated protein 2 (MAP2) or

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tubulin.
Increasing evidence shows that adult neurogenesis in the neuro-
genic regions (subventricular zone and subgranular zone of the den-
tate gyrus) may be dysregulated in AD, which may be linked to
age-dependent memory loss [ 91 , 92 ]. APP/PS1 mice also show a sig-
nifi cant inhibition of neurogenesis [ 86 , 93 , 94 ]. Neurogenesis may be
assessed using markers such as doublecortin (Dcx, a marker of newly
generated neurons), nestin (a marker of neuronal precursor cells),