Plaque-induced neurite abnormalities: Implications for disruption of neural networks in Alzheimer’s disease

Abstract

The brains of Alzheimer's disease patients contain extracellular A␤ amyloid deposits (senile plaques). Although genetic evidence causally links A␤ deposition to the disease, the mechanism by which A␤ disrupts cortical function is unknown. Using triple immunof luorescent confocal microscopy and three-dimensional reconstructions, we found that neuronal processes that cross through an A␤ deposit are likely to have a radically changed morphology. We modeled the electrophysiological effect of this changed morphology and found a predicted delay of several milliseconds over an average plaque. We propose that this type of delay, played out among thousands of plaques throughout neocortical areas, disrupts the precise temporal firing patterns of action potentials, contributing directly to neural system failure and dementia.Alzheimer's disease (AD) causes a clinical syndrome marked by severe, progressive dementia. Neuropathological changes include A␤ deposits that are often associated with dystrophic neurites (neuritic plaques), dystrophic neurites in the neuropil (neuropil threads), and neurofibrillary tangles. Inheritance of mutations in the amyloid protein precursor lead to changes in the generation of A␤, extracellular deposition of A␤ in the brain, and an autosomal dominant early onset form of AD (1-3), suggesting that A␤ is a critical early component of the pathophysiological cascade. However, whether A␤ deposition causes neural system failure is controversial. Brains of nondemented elderly individuals frequently contain numerous A␤ deposits (4). Even in AD, where A␤ deposits can occupy as much as 15% of the cortical surface area, the amount of A␤ deposits correlates poorly with clinical severity or duration of disease (5-7).It has been shown that A␤ deposits do not correlate with local neuronal loss (7,8). We now examine their effect on neuronal processes. We observe that neurites that pass through A␤ deposits in AD lose their normal characteristic straight shape. This change in geometry has marked consequences in terms of signal transduction properties of dendrites as judged by cable-theory simulations; delays in the millisecond range would be expected as a dendrite passes through a plaque. Insofar as any individual process passes through a variable number of plaques en route from synapse to cell body, we postulate that plaques distributed in widespread neocortical areas lead to a disruption of synchronous activation of neural systems and a stochastic breakdown in the integration of limbic and association cortices needed to form coherent evocation of memory-related events (9). MATERIALS AND METHODSPatient Selection. All cases were monitored at the Massachusetts General Hospital Alzheimer's Disease Research Center. Seven patients had clear clinical histories of AD dementia with well documented duration of disease and had a confirmed neuropathological diagnosis of AD without evidence of vascular insults (10), cortical Lewy bodies, or other dementiarelated lesions. General neuropathological examination include...

New techniques for imaging, digitization and analysis of three-dimensional neural morphology on multiple scales

“…12I). These observations are comparable to previous findings in other AD mouse models (Knowles et al, 1999;Le et al, 2001;Tsai et al, 2004). However, until precise 3D models of these geometric distortions are produced, investigations of their functional effects (e.g.…”

“…In Alzheimer's disease (AD) for example, amyloid beta protein exists in many molecular forms, and eventually aggregates into the insoluble plaques that are one of the neuropathological hallmarks of AD. Insoluble amyloid deposits comprising extracellular accumulations of amyloid beta peptide and other proteins surrounded by degenerating axons and dystrophic dendrites are an example of general histopathologic lesions that can physically distort neuronal processes in their vicinity, which must take tortuous routes around the lesions, resulting in characteristic distortions of local and global dendritic geometry (Knowles et al, 1999;Le et al, 2001;Urbanc et al, 2002). In addition, spines are often lost as spiny dendrites traverse a plaque, dendritic shafts undergo atrophy and axons in the vicinity of plaques develop varicosities (Tsai et al, 2004).…”

Substrate‐Bound β‐Amyloid Peptides Inhibit Cell Adhesion and Neurite Outgrowth in Primary Neuronal Cultures

“…Recent studies demonstrate that structural remodeling of synapses involving the growth of new dendritic projections may be the mechanism for long-term behavioral learning or memory (Engert and Bonhoeffer, 1999). Studies by Knowles et al (1999) suggest that amyloid-induced structural abnormalities in neuronal processes are sufficient to disturb temporal firing patterns, thereby contributing to memory loss and dementia.…”

Two-photon imaging of synaptic plasticity and pathology in the living mouse brain

“…[48][49][50] However, only A␤ deposition in certain areas but not others correlates well with the degree of cognitive dysfunction. 46,[51][52][53][54][55] Furthermore, in transgenic mouse models of AD it has been shown that cognitive dysfunction may occur even before plaque deposition. 56 This and other findings have raised the possibility that soluble forms of amyloid oligomers can have an important role in initiating the disease possibly by targeting synapses.…”