Neurofibrillary degeneration of cholinergic and noncholinergic neurons of the basal forebrain in Alzheimer's disease

Abstract

Two principal features of Alzheimer's disease (AD) are (1) the occurrence of neurofibrillary tangles (NFTs) and senile plaques, and (2) the loss of cortical cholinergic activity because of dysfunction of neurons in the basal forebrain cholinergic system. The relationship of these two abnormalities is an unresolved issue in the pathology of AD. We used polyclonal antibodies specific for paired helical filaments (PHFs), combined with acetylcholinesterase (AChE) histochemistry, to assess the cytoskeletal changes of cholinergic and noncholinergic neurons in the basal forebrain in AD. In both sporadic and familial AD, the nucleus basalis of Meynert (nbM) showed a marked decrease in AChE-positive (AChE+) perikarya and abundant immunoreactive NFTs. In double-labeling studies of the nbM, PHF reactivity was found both in surviving AChE+ neurons and in many AChE- NFTs that were not associated with microscopically recognizable cell structures. Some surviving AChE+ perikarya did not contain NFTs. Numerous NFTs and senile plaques were identified by PHF immunoreactivity in other basal forebrain areas, including subnuclei of the amygdala that showed low or absent AChE activity. We conclude that the dysfunction and death of cholinergic neurons in the nbM is associated with extensive NFT formation, including apparently residual NFTs in loci where nbM neurons once existed; and many noncholinergic neurons and neurites in the basal forebrain show NFT and senile plaque formation. The cytopathology of AD involves neurons of varying transmitter specificities, including cholinergic neurons in the basal forebrain.

Selective deposition of amyloid-? protein in the entorhinal-dentate projection of a transgenic mouse model of alzheimer's disease

“…The regional distribution of amyloidosis in PDAPP mouse is remarkably similar to that of AD (Hyman et al, 1986;Rasool et al, 1986). Therefore, it is conceivable that the neurotransmitter system in the perforant path plays a similar role in selectivity of A␤ deposition/plaque formation in AD.…”

Activating the damaged basal forebrain cholinergic system: tonic stimulation versus signal amplification

“…Therefore, stimulation of activity within residual cholinergic neurons by GABAergic disinhibition may expedite such a process. The autocannibalism theory, however, is not consistent with increasing scepticism regarding the selective vulnerability of cholinergic neurons (Rasool et al 1986). Furthermore, the lack of effect of choline and phosphatidylcholine supplementations in SDAT patients (e.g., Drachman et al 1982) does not follow the predictions made on the basis of this theory.…”

“…Another increasingly popular belief indicates that the cholinergic hypothesis represents an oversimplified concept of the biological basis of dementia. While "it is difficult to argue with the inherent wisdom of this position" (Bartus et al 1985, p 425), and while a selective vulnerability of cholinergic neurons in SDAT seems questionable (Rasool et al 1986), there is overwhelming evidence for a relationship between the decline in cognitive abilities and markers of cortical cholinergic activity. No such relationship has been demonstrated for other neurotransmitters (Palmer et al 1987a, b, c;Lowe et al 1988;).…”

Excessive Expression of Acetylcholinesterase Impairs Glutamatergic Synaptogenesis in Hippocampal Neurons

“…Its fundamental role at cholinergic synapses is to terminate neurotransmission by rapid hydrolysis of acetylcholine (Massoulie, 2002). Independent of its catalytic function, AChE exhibits multiple biological actions on neuronal cell differentiation (Schlaggar et al, 1993;Coleman and Taylor, 1996), adhesion (Johnson and Moore, 2000;Sharma et al, 2001), neuritogenesis (Koenigsberger et al, 1997;Grifman et al, 1998;Bigbee et al, 2000), and neurodegeneration in some pathological processes, such as Alzheimer's disease (Rasool et al, 1986;Parnetti et al, 2002). Excess AChE emerges under conditions of stress (Meshorer et al, 2002;Nijholt et al, 2004) and exposure to AChE inhibitors (Kaufer et al, 1998).…”