Does Alzheimer's disease begin in the brainstem?

Abstract

Although substantial evidence indicates that the progression of pathological changes of the neuronal cytoskeleton is crucial in determining the severity of dementia in Alzheimer's disease (AD), the exact causes and evolution of these changes, the initial site at which they begin, and the neuronal susceptibility levels for their development are poorly understood. The current clinical criteria for diagnosis of AD are focused mostly on cognitive deficits produced by dysfunction of hippocampal and high-order neocortical areas, whereas noncognitive, behavioural and psychological symptoms of dementia such as disturbances in mood, emotion, appetite, and wake-sleep cycle, confusion, agitation and depression have been less considered. The early occurrence of these symptoms suggests brainstem involvement, and more specifically of the serotonergic nuclei. In spite of the fact that the Braak and Braak staging system and National Institutes of Aging - Reagan Institute (NIA-RI) criteria do not include their evaluation, several recent reports drew attention to the possibility of selective and early involvement of raphe nuclei, particularly the dorsal raphe nucleus (DRN), in the pathogenesis of AD. Based on these findings of differential susceptibility and anatomical connectivity, a novel pathogenetic scheme of AD progression was proposed. Although the precise mechanisms of neurofibrillary degeneration still await elucidation, we speculated that cumulative oxidative damage may be the main cause of DRN alterations, as the age is the main risk factor for sporadic AD. Within such a framework, beta-amyloid production is considered only as one of the factors (although a significant one in familial cases) that promotes molecular series of events underlying AD-related neuropathological changes.

Fig. 1

Illustration of neurofibrillary changes, which in AD spread in an anterograde fashion through identified neuronal circuits due to yet unknown cause(s). All figures were obtained using the mouse monoclonal antibody AT8 (Innogenetics, Temse, Belgium) used at a 1:200 dilution in indirect immunocytochemistry. It should be stressed that AT8 reacts with tau only when multiple sites around Ser202, including Ser199, Ser202, and Thr205, are phosphorylated. Single phosphorylation of any of these residues is not enough for AT8 reactivity. Thus, AT8 immunoreactivity is useful in detecting phosphorylation of Ser202/Ser202/Thr205 for proline-directed kinases. a. Left hippocampus of 73-year old AD man who fulfilled NINCDS-ADRDA and DSM-IV-TR clinical criteria for AD and had a 7-year history of slowly progressive cognitive deterioration and various behavioral symptoms (middle level of hippocampal body, cause of death was bronchopneumonia), black arrowheads show perforant pathway fibers (originating from layer II islands of entorhinal cortex) that contact the apical dendrites of CA1 pyramidal neurons directly, open arrows denote subicular axons, magnification 18.75x; b. Right hippocampus of 83-year old woman with AD (middle level of hippocampal body), who had behavioral and memory problems for 5.5 years before death from myocardial infarction and was also fulfilling NINCDS-ADRDA and DSM-IV-TR clinical criteria for AD; c. Left hippocampus of the same case as in a; black arrowheads delineate CA2 region (most tangle-bearing neurons are not AT8-immunoreactive). Legend: prosub, prosubiculum; EC, entorhinal cortex; magnification 10x. d. Beaded-like appearance of AT8-positive axons, same subject as in a and c, scale bar = 10 μm, e. Early neurofibrillary changes of a temporal neocortex layer V pyramidal neuron, scale bar = 100 μm.

Fig. 2

Tau protein phosphorylation during fetal brain development. a. Western blot of tau protein at 11weeks of gestation (w.g.) using monoclonal antibody AT8. Arrow shows positive bands from all three regions examined, particularly the frontal lobe, b. Arrow points to prominent AT8-immunoreactivity in the lower subplate zone of the frontal regions of the telencephalon at 18 w.g., c. At 20 w.g. AT8-immunoreactivity moves from lower to the upper subplate zone, d. During mid-gestation, the fornix as well as subset of callosal commissural fibers are unambiguously AT8-immunoreactive, whereas the hippocampal formation and internal capsule remained unstained; AT8-immunoreactivity then gradually appears in the cortical plate, diminishing and disappearing completely from the subplate zone at the end of 32 w.g. Fetal brains were part of the Zagreb Neuroembryological collection. Legend: M, mesencephalon, O, occipital lobe, F, frontal lobe, CP, cortical plate, SP, subplate, CI, internal capsule, GE, ganglionic eminence, CC, corpus callosum, Fx, fornix, HF, hippocampal formation, scale bars in b, c and d = 1 cm.

Fig. 3

Gallyas silver iodide staining of the dorsal part of the supratrochlear subnucleus of the dorsal raphe nucleus of a mildly cognitively impaired 69-year old woman. This method specifically stains paired helical filaments (PHFs) in neurofibrillary tangles (NFTs) (arrows) and degenerated neurites (arrowheads). An initial degree of Gallyas-positive cytoskeletal changes in the dorsal part of ST DRN is seen. Legend: ST DRN, supratrochlear subnucleus of the dorsal raphe nucleus; aq, cerebral aqueduct (of Sylvius). Scale bar = 100 μm.