Apoptotic signals within the basal forebrain cholinergic neurons in Alzheimer's disease.
A relatively early and substantial loss of basal forebrain cholinergic neurons is a constant feature of Alzheimer's disease (AD). However, the mechanisms that contribute to the selective vulnerability of these neurons are not fully delineated. In the present series of experiments, we determined the possible contribution of apoptotic processes and other pathologic cascades to the degeneration of the cholinergic neurons of the nucleus basalis of Meynert (NBM) in AD. In contrast to neurons in the frontal cortex which showed prominent DNA fragmentation as detected by the TUNEL method, no DNA fragmentation was observed within the NBM in any of the AD or normal brains. Similarly, immunoreactivity for the apoptotic signals Fas, Fas-ligand, Bax, Bcl-x, caspase-8, caspase-9 and caspase-3 was absent from the NBM of AD and control brains. In contrast, a substantial subpopulation of cholinergic neurons within the NBM in AD displayed prominent immunoreactivity for the apoptotic signal Fas-associated death domain (FADD) in the form of tangles. FADD immunoreactivity was also present in dystrophic neurites. FADD-positive tangle-like structures were localized in neurons which contained immunoreactivity for the cholinergic marker choline acetyltransferase (ChAT) and the low affinity neurotrophin receptor p75NTR. While many of the NBM cholinergic neurons in control brains contained immunoreactivity for the calcium binding protein calbindin-D28K (CB), the NBM neurons in AD displayed a substantial loss of CB immunoreactivity. Importantly, most of FADD-immunoreactive cholinergic neurons were devoid of CB immunoreactivity, and, conversely, most CB-positive cholinergic neurons had no FADD immunoreactivity. FADD immunoreactivity within the basal forebrain was colocalized with phosphorylated tau immunoreactive tangles and dystrophic neurites. In contrast, FADD immunoreactivity did not appear to be related to the primarily diffuse amyloid-beta deposits intermingled between cholinergic neurons in AD NBM. Finally, many CD68-positive microglia were observed surrounding the NBM cholinergic neurons in AD. In conclusion, the findings of the present study indicate that, while the FADD apoptotic signaling pathway may be triggered within the basal forebrain cholinergic neurons in AD, the apoptotic cascade is most likely aborted as no DNA fragmentation was detected and the executioner caspase-3 was not up-regulated within these neurons. The findings also suggest possible relationships between loss of CB, FADD expression and phosphorylation of tau within the basal forebrain cholinergic neurons in AD.
Wu
Chuang-Kuo
CK
Alzheimer Disease and Memory Disorders Center, Department of Neurology, Memorial Hospital of Rhode Island, 111, Brewster Street, Pawtucket, RI 02860, USA. John_Wu@mhri.org
Thal
Leon
L
Pizzo
Donald
D
Hansen
Lawrance
L
Masliah
Eliezer
E
Geula
Changiz
C
D000109:Acetylcholine / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology* / Q000503:physiopathology*; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D029681:Arabidopsis Proteins / Q000378:metabolism; D064092:Calbindin 1; D064026:Calbindins; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D053938:DNA Fragmentation / Q000502:physiology; D044943:Fatty Acid Desaturases / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D007211:Indoles; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D016548:Prosencephalon / Q000473:pathology*; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000097382:CD68 Molecule
D000109:Acetylcholine; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D029681:Arabidopsis Proteins; D064092:Calbindin 1; D064026:Calbindins; D002795:Choline O-Acetyltransferase; D044943:Fatty Acid Desaturases; D007211:Indoles; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D064030:S100 Calcium Binding Protein G; C576498:CALB1 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C576500:Calb1 protein, rat; C105521:Slc15a4 protein, rat; C007293:DAPI; C084083:Fad7 protein, Arabidopsis