Reasons For Synaptic Decline In Ad

The amyloid cascade hypothesis states that amyloid precursor protein (APP) and presenilin (PS) mutations combine to promote the formation of a highly insoluble amyloid beta (AP) and that the progressive accumulation of AP triggers neuronal and synaptic abnormalities associated with AD. Normally, APP is transported within cells, such as neurons, in a rapid anterograde fashion that accumulates in presynaptic terminals, where it most likely plays a role in cell adhesion. It is primarily processed through a nonamyloidogenic pathway in which cleavage occurs at the a-secretase site and the fragments are degraded. Cells that have mutant APP show increased AP as a result of cleavage at the P or y secretase site. It is unclear if amyloid load correlates with changes in synaptic numbers. There is now evidence that a soluble form of amyloid-P (sAP) is also found in brain tissue of normal and AD patients82. sAP demonstrates a high correlation with synaptic loss in both a transgenic (tg) animal model of AD and in AD patients83,84.

Oxidative stress and damage have also been implicated as a fundamental process involved in the pathogenesis of AD85,86. Oxidative damage is one of the earliest events in AD with some evidence that levels diminish with duration of the disease. It might be the case that sAP accumulates early in the disease process and accelerates the formation of oxidative damage in synaptic terminals, ultimately impairing their function by affecting synaptic mitochondria and synaptic proteins eventually leading to synaptic loss.

The identification of the APP and PS mutations has allowed researchers to create tg animals with these mutant genes to gain a better understanding of cellular events that may underlie AD. Besides the overexpression of AP and amyloid deposits, tg mice also have many other histopathologic features, including activated microglia, reactive astrocytes, dystrophic neuritis, oxidative damage, and vascular amyloid. While most of the tg mouse models to date have not successfully demonstrated NFT or paired helical filaments, there are several animals that may have evidence of phosphorylated tau.

Transgenic mouse models that purport to be models of AD should demonstrate significant declines in synaptic numbers within regions that are known to be affected in the disease. In reviewing the current literature concerning tg models, it is surprising that while some studies report mild-to-moderate decreases84,87-91, others report no change92-99, or even significant increases100-102 in markers of presynaptic boutons. These controversial results cannot be attributed to differences in presynaptic markers or the techniques employed since the majority of the studies use immunohistochemistry to stain for synaptophysin. These results question exactly what role amyloid may play in AD-related synaptic loss. It is also interesting that many of the tg mouse models also do not demonstrate significant changes in learning and memory.

One of the more current theories for the loss of synapses revolves around a preferential decline in axoplasmic flow. The accumulation of tau can block the transport of organelles in neurons by inhibiting the kinesin-dependent transport system. With the progressive buildup of paired helical filaments interacting with straight filaments the cytoskeleton of the neuron is disrupted, resulting in inhibited axoplasmic flow. The result would be a "starvation" of the synaptic terminals and eventually lead to not only synaptic loss but death of the neuron103,104. It has recently been demonstrated that with AD there is a significant reduction in vesicle trafficking-related genes105. Failure to dock specific synaptic vesicles would interfere with neurotransmitter release and synaptic connectivity resulting in a decline in cognitive function.

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