Dendritic Spine Abnormalities in Amyloid Precursor Protein Transgenic Mice Demonstrated by Gene Transfer and Intravital Multiphoton Microscopy

Abstract

Accumulation of amyloid-␤ (A␤) into senile plaques in Alzheimer's disease (AD) is a hallmark neuropathological feature of the disorder, which likely contributes to alterations in neuronal structure and function. Recent work has revealed changes in neurite architecture associated with plaques and functional changes in cortical signaling in amyloid precursor protein (APP) expressing mouse models of AD. Here we developed a method using gene transfer techniques to introduce green fluorescent protein (GFP) into neurons, allowing the investigation of neuronal processes in the vicinity of plaques. Multiphoton imaging of GFP-labeled neurons in living Tg2576 APP mice revealed disrupted neurite trajectories and reductions in dendritic spine density compared with age-matched control mice. A profound deficit in spine density (ϳ50%) extends ϳ20 m from plaque edges. Importantly, a robust decrement (ϳ25%) also occurs on dendrites not associated with plaques, suggesting widespread loss of postsynaptic apparatus. Plaques and dendrites remained stable over the course of weeks of imaging. Postmortem analysis of axonal immunostaining and colocalization of synaptophysin and postsynaptic density 95 protein staining around plaques indicate a parallel loss of presynaptic and postsynaptic partners. These results show considerable changes in dendrites and dendritic spines in APP transgenic mice, demonstrating a dramatic synaptotoxic effect of dense-cored plaques. Decreased spine density will likely contribute to altered neural system function and behavioral impairments observed in Tg2576 mice.

Stereologic estimates of total spinophilin-immunoreactive spine number in area 9 and the CA1 field: Relationship with the progression of Alzheimer's disease

“…Similarly, Callahan et al [9] documented a progressive reduction of synaptophysin mRNA in single NFT-bearing neurons. In the context of the possible disconnection of corticocortical pathways in AD [30,32,48], dendritic spine pathology is thought to be secondary to abnormal afferent innervation [20,63,65,81]. In line with this hypothesis, Scheff et al reported in the only stereologic study available in this field a weak positive relationship between NFT densities in layer II of the entorhinal cortex and loss of synaptic contacts in the outer molecular layer of dentate gyrus (i.e.…”

“…Although postsynaptic components are thought to be affected in early-onset AD [14,65], few studies have explored in humans the status of dendritic spines in brain aging. Spines are dynamic structures that are the proposed site of synaptic plasticity underlying learning and memory [34,49,62].…”

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

“…Thus, downstream events that may be directly or indirectly related to Aβ or tangle formation may lead to neuronal dysfunction and cognitive decline. For example, synaptic dysfunction may be a consequence of APP overexpression or increased Aβ [58,60], or other pathological molecular cascades may be engaged in DS that are associated with AD pathology such as neuroinflammation [18,19,21,59], endosomal dysfunction [6,7] and oxidative damage [45,46]. When these temporal events are considered together, DS involves the co-occurrence of features of aging and of AD pathogenesis.…”

Rapid, concurrent alterations in pre- and postsynaptic structure induced by naturally-secreted amyloid-β protein

“…Alterations in spine number and shape are associated with cognitive deficits in neuropsychiatric disorders and mental retardation syndromes (Blanpied and Ehlers, 2004). Dendritic spine loss has been documented in AD and in animal models, but previous studies associated such spine loss with late stages of the disease when amyloid plaques are present (Baloyannis, et al, 1992;Davidsson and Blennow, 1998;Einstein, et al, 1994;Ferrer and Gullotta, 1990;Moolman, et al, 2004;Probst, et al, 1983;Spires, et al, 2005). However, recent studies in young TG2576 transgenic mice expressing the APP-Swedish mutation observed reduced spine density prior to plaque deposition, suggesting that soluble forms of Aβ might confer synaptotoxic changes (Jacobsen, et al, 2006;Lanz, et al, 2003).…”