Neurotrophic factors in Alzheimer's disease: pathogenesis and therapy.

Alzheimer's disease (AD) is a common neurodegenerative disease with a prevalence estimated to reach 115 million by 2050. It is characterized by abnormal extracellular accumulation of amyloid­beta (Aß) peptide and intracellular neurofibrillary tangles (NFTs) that result in neuro­inflammation, synaptic dysfunction, neurotransmitter imbalance, neuronal loss, and dendritic changes. A hypothesis of neurotrophic factor (NTF) involvement in neurodegenerative diseases and their potential as a therapeutic tool has emerged. There are wide information gaps on this topic. However, consistent with this hypothesis, AD may be caused by a deficiency in neurotrophin proteins or receptors expression. In AD brains, an increase in nerve growth factor and a decrease in brain-derived neurotrophic factor in the hippocampus and certain neocortical regions, and a decrease in TrkA in the cortex and nucleus basalis has been observed. Thus, comparative data relating to recent hypotheses addressing NTF content and receptors in experimental animals and human brains, along with their potential roles in the treat ment of AD, are discussed in this review.

Quantitative Three-Dimensional Reconstructions of Excitatory Synaptic Boutons in the "Barrel Field" of the Adult "Reeler" Mouse Somatosensory Neocortex: A Comparative Fine-Scale Electron Microscopic Analysis with the Wild Type Mouse.

Synapses are key structural determinants for information processing and computations in the normal and pathologically altered brain. Here, the quantitative morphology of excitatory synaptic boutons in the "reeler" mutant, a model system for various neurological disorders, was investigated and compared with wild-type (WT) mice using high-resolution, fine-scale electron microscopy (EM) and quantitative three-dimensional (3D) models of synaptic boutons. Beside their overall geometry, the shape and size of presynaptic active zones (PreAZs) and postsynaptic densities (PSDs) forming the active zones and the three pools of synaptic vesicles (SVs), namely the readily releasable pool (RRP), the recycling pool (RP), and the resting pool, were quantified. Although the reeler mouse neocortex is severely disturbed, no significant differences were found in most of the structural parameters investigated: the size of boutons (~3 µm2), size of the PreAZs and PSDs (~0.17 µm2), total number of SVs, and SVs within a perimeter (p) of 10 nm and p20 nm RRP; the p60 nm, p100 nm, and p60-p200 nm RP; and the resting pool, except the synaptic cleft width. Taken together, the synaptic organization and structural composition of synaptic boutons in the reeler neocortex remain comparably "normal" and may thus contribute to a "correct" wiring of neurons within the reeler cortical network.

Ultrastructural heterogeneity of layer 4 excitatory synaptic boutons in the adult human temporal lobe neocortex.

Synapses are fundamental building blocks controlling and modulating the 'behavior' of brain networks. How their structural composition, most notably their quantitative morphology underlie their computational properties remains rather unclear, particularly in humans. Here, excitatory synaptic boutons (SBs) in layer 4 (L4) of the temporal lobe neocortex (TLN) were quantitatively investigated. Biopsies from epilepsy surgery were used for fine-scale and tomographic electron microscopy (EM) to generate 3D-reconstructions of SBs. Particularly, the size of active zones (AZs) and that of the three functionally defined pools of synaptic vesicles (SVs) were quantified. SBs were comparatively small (~2.50 µm2), with a single AZ (~0.13 µm2); preferentially established on spines. SBs had a total pool of ~1800 SVs with strikingly large readily releasable (~20), recycling (~80) and resting pools (~850). Thus, human L4 SBs may act as 'amplifiers' of signals from the sensory periphery, integrate, synchronize and modulate intra- and extracortical synaptic activity.