Synaptic pathology in the brain cortex of old monkeys as an early alteration in senile plaques formation
C. Bertoni-Freddari, P. Fattoretti, T. Casoli, G. Di Stefano, B. Giorgetti, Y. Grossi, M. Balietti and G. Perretta*
Neurobiology of Aging Laboratory INRCA Research Department, Via Birarelli 8, 60121 Ancona, Italy and *Istituto di Neurobiologia e Medicina Molecolare-CNR, S.p Anguillarese km 1.3, 00060 Roma, Italy
Senile plaques (SP) are alterations of the senile brain particularly
prominent in Alzheimers disease (AD). The classical plaque appears as a
roughly spherical area in the neuropil consisting of a compact core or
of narrow bundles of beta amyloid (bA), between abnormal neurites.
Although SP formation is reported to occur over years, in the human
brain this process can be studied only at autopsy and this constitutes
a great limit to obtain results specifically regarding the steps of SP
build up. Monkeys are reported to develop SP progressively from the
age of 15 years, thus these animals represent a good animal model to
investigate SP formation dynamics over time and the eventual
age-associated changes favouring this process. Synaptic junctions have
been documented to undergo significant alterations both in aging and
AD, thus an impaired synaptic function may constitute a precocious step
in the development and progression of SP. On the basis of this
assumption, a computer-assisted morphometric study has been carried out
on ethanol phosphotungstic acid (E-PTA) stained synaptic junctions in
the frontal and temporal brain cortex of adult and aged monkeys
(Macaca fascicularis) with the aim of identifying early signs of
synaptic pathology in aging. The average synaptic size (area: S), the
synaptic numeric density (Nv: number of contacts/mm3 of tissue), the
synaptic surface density (Sv: overall area of synaptic contacts/mm3 of
tissue) and the number of synapses/neurone (Syn/Neur) were the measured
ultrastructural parameters. At a comparison with adult animals, both in
frontal and temporal cortex of aged animals Nv was decreased and S was
increased at a not significant extent, while Sv was unchanged in the
temporal cortex and not significantly increased in the temporal cortex.
In aged monkeys Syn/Neur was decreased by 16.4% in the temporal cortex
and it was increased by 12.3% in the frontal cortex. The present
findings confirm and extend previous results from the human brain in
normal aging and AD, i.e. the age-related loss of synaptic contacts is
associated with an increase in synaptic size. A percent distribution of
S showed that in the frontal cortex of old animals the fraction of
enlarged contact zones (0.2mm2>) accounts for more than 27.5% vs. 16.9%
found in adult monkeys, while in the temporal cortex the larger
contacts in old animals account for more than 32.5% vs. 21.3% found in
adults. The opposite results of Syn/Neur observed in the two areas of
the brain cortex deserves a specific comment. Since synapses and
neurones are counted in the same area of the brain cortex, the Syn/Neur
value is independent from any change in tissue volume (e.g. shrinkage)
due either to age or experimental processing; thus, this parameter
reliably reports on the real situation in the tissue. Accordingly, the
present findings suggest that the temporal cortex appears to be more
vulnerable to aging than the frontal cortex. Tenable interpretations of
the present data must take into account the sequence of steps currently
suggested to occur in the functional remodelling of synaptic
ultrastructure. Namely, as a consequence of repeated stimulation,
synaptic junctions may undergo a two, three-fold enlargement of their
normal size (S) and, if stimulation proceeds, the larger contact zones
perforate and split into smaller junctional areas that, in turn, can
be reinforced or degraded according to the functional conditions of the
neural network where they are located. This cycle of events is reported
to be an ongoing adaptive process purported to modulate synaptic number
and size according to stimulations coming from the individuals
experiential framework; thus, any impairment and/or delay in the rate
of this physiological synaptic turnover may result in a functional
decay. On the basis of this cycle of events, the consistent increase
of the fraction of enlarged contacts in the brain cortex of aged
animals suggests that the synaptic remodelling process proceeds at a
slower rate in aging or is halted at the early step of the enlargement
of the junctional areas. Moreover, we found that in the temporal cortex
the percent of perforated junctions is the same in both the age groups
(3.8% and 4.0%), while in the frontal cortex of old monkeys it is twice
as much the value of the adults (7.1% vs. 3.5%, respectively):
according to the remodelling cycle described above, this increased
percent of the fraction of synapses at the step of perforation suggests
that in the frontal cortex synaptic rearrangement appears to occur at a
higher extent or to proceed at a faster rate. The temporal cortex of
the aged Macaca fascicularis is reported to be particularly sensitive
to SP formation and our data confirm this vulnerability, thus lending
further support to the involvement of synaptic subtle pathology in the
development and progression of these alterations typical of the human
and primate brain cortex.
Key words:
Plaques, Synapses, Morphometry, Alzheimer disease, Macaca fascicularis
Problems or questions regarding this site should be directed to
the organiser