Spatial patterns of mammalian brain aging: Distribution of cathepsin D–immunoreactive cell bodies and dystrophic dendrites in aging dogs resembles that in Alzheimer's disease

Abstract

Elevated levels of the lysosomal enzyme cathepsin D are found in the early stages of Alzheimer's disease (AD) and co-occur with intraneuronal tangles. The present study tested whether increases in cathepsin D would emerge during aging in another mammalian species. Regional brain patterns of cathepsin D immunostaining were compared in dogs ages 0.35 to 16 years. Accumulations of immunopositive material were evident in neuronal cell bodies in many forebrain sites in middle-age to old dogs (>/=6 years). Three types could be distinguished: (1) dense aggregates with no particular position within the cell body; (2) crescent-shaped "caps" that occupied one pole of the cell body; and (3) very dense "spikes" that extended from the cell body for variable distances into the apical dendrite; these spikes were found in only a few areas, most notably the subiculum and layer V of neocortex. The spikes appeared between ages 2 and 5 years and increased steadily with age thereafter. Spikes were found in the subiculum in the aged human brain but only infrequently; they were, however, present in large numbers in AD brains. These results established that brain aging in dogs is (1) well advanced by middle age, (2) varies markedly across regions, and (3) in at least some of its aspects (dystrophic dendrites) is prominent in areas known to exhibit pathology early in the course of AD. Combined with previous results for rats, these findings indicated that changes in cathepsin D observed in AD, in particular in the temporal lobe, reflect a generalized mammalian pattern of brain aging.

Cellular Responses to Protein Accumulation Involve Autophagy and Lysosomal Enzyme Activation

“…15,41,42 While the hippocampal slice model has identified an association between protein accumulation and synaptopathogenesis, 32,37 slice cultures show that lysosomal activation occurs as well (Fig. 5A).…”

Synaptic plasticity in early aging

“…First, conditions that interfere with normal operation cause lysosomes to proliferate, something that in some neurons leads to large accumulations of fused, dense secondary bodies in the periphery of the cell body. This process appears to be responsible for the formation of meganeurites (Bednarski et al, 1997) and similar structures found in primary dendrites ('dendritic spikes', Bi et al, 2003). These pathological features likely disrupt transport between the cell body and its processes by displacing and distorting the tubule system.…”

Autophagic-Lysosomal Dysfunction and Neurodegeneration in Niemann-Pick Type C Mice: Lipid Starvation or Indigestion?

“…Increases in autophagosomes/autolysosomes were confirmed by electron microscopy analysis, as numerous membranous vacuoles with double membranes or multilamellar electron-dense material are observed in the cytoplasm of Purkinje cells in Npc1 -/-mice. We previously reported changes in lysosomal function in the brains of middle-aged and aged mammals, 20,21 and decreases in lysosomal function have been hypothesized to produce increases in autophagosomes in brains with Alzheimer's disease. 22,23 It is thus conceivable that changes in lysosomal function induced by accumulation of cholesterol in Npc1 -/-brains reduce the turnover of autophagic vacuoles leading to a buildup of these organelles.…”