Biology Reference
In-Depth Information
Neuroplasticity and synapses: Alzheimer's disease as a case in point
Twenty-five percent of individuals over 65 years of age have sufficient cognitive
problems, short of dementia, to affect the quality of their lives [Unverzagt et al., 2001]. The
ability to learn consciously and recall new information is one of the areas most affected
during aging. Yet, our knowledge about the factors that predispose a person to age-associated
cognitive problems remains fragmented. The balance between dynamic stabilization and
destabilization of synapses may provide the basis for failure of plasticity with age and
disease. In vivo, synaptogenesis rates decline with developmental age, and there is
recapitulation of developmental gene expression responses in adult lesion [Styren
et al.,
1999]
and aging, including AD [Kondo
et al.,
1996]. If mechanisms controlling developmental
plasticity were to be defective and later reactivated (e.g. in aging, mild cognitive impairment
in early AD, or clinically diagnosed AD), they might contribute to ineffective plasticity
responses and exacerbate the plasticity burden of aging and AD. The differential
susceptibility of AD-specific regions and neurons may, indeed, be related to the degree of
retained capacity for plastic remodeling [Arendt
et al.,
1998].
AD is an aging-dependent neurodegenerative disorder characterized by two main
neuropathological hallmarks in the brain: deposition of insoluble fibrillar Aβ (amyloid β-
peptide) in extracellular plaques; aggregated hyperphosphorylated tau protein, which is found
largely in the intracellular neurofibrillary tangles [Selkoe and Schenk, 2003]. Aβ is generated
by sequential proteolytic cleavage of amyloid precursor protein (APP). The non-
amyloidogenic pathway involves cleavage by α-secretases, while the amyloidogenic pathway
involves cleavage by β- and γ-secretases [Jarrett
et al.,
1993; De Strooper
et al.,
2000]. Aβ
generated by γ-secretase activity can vary in length: the most common forms contain 38, 40
or 42 amino acids. Because of the two additional amino acids isoleucine and alanine, Aβ
1-42
aggregates more quickly than Aβ
1-40
[Grimm
et al.,
2007] and is the major component of
neuritic plaques in AD. The relevance of Aβ
1-42
in AD is further supported by familial forms
of AD. Most of the missense mutations in the genes encoding APP and presenilin increase the
production of Aβ
1-42
. There is now extensive evidence that abnormal processing of Aβ, as a
result of altered production by β-secretase and γ-secretase cleavage of amyloid precursor
protein (APP) or impaired Aβ clearage mechanisms, leading to the accumulation of toxic
aggregates, is a causal factor in AD [Hardy and Selkoe, 2002]. The thesis that synaptic
memory mechanisms are a consequence of Aβ-induced dysfunction will be discussed further
on.
Synaptic loss in the hippocampus and neocortex is an early event and is the major
structural correlate of cognitive dysfunction in AD [Gonatas
et al.,
1967; Davies
et al.,
1987;
Scheff
et al.,
1990; Terry
et al.,
1991; DeKosky
et al.,
1996; Masliah, 1998; reviewed in
Arendt, 2001]. Synaptic pathology is reflected by a loss of all major components of small
synaptic vesicles and most peptides, accompanied by extensive aberrant changes of the
synapse [Lassmann
et al.,
1993]. The bulk of neocortical synaptic loss most likely derives
from loss of cortico-cortical associational fibers [Morrison
et al.,
1990], rather than
degeneration of subcortical input [Arendt
et al.,
1995b]. Synapse and dendrite loss in AD
exceeds that seen with normal aging [Terry
et al.,
1994]. AD is a slowly progressing disorder,
Synaptic degeneration, like early AD, is a slow process progressing from an initially
reversible functionally responsive stage of down-regulation of synaptic function to stages
