Evidence that immunoglobulin-positive neurons in Alzheimer's disease are dying via the classical antibody-dependent complement pathway

Abstract

A recent study provided evidence that immunoglobulins (Igs) are not only present in Alzheimer's disease (AD) brains, but are also immunohistochemically detected in and/or on a particular population of pyramidal neurons that appeared morphologically degenerative in contrast to neighboring normal-appearing Ig-negative neurons.¹ Because little has been reported about these Ig-positive neurons, the objectives of this study were to characterize the inflammatory profile of these neurons in the AD brain by determining if they possess complement components and are associated with reactive microglia. The data showed that the Ig-positive neurons had complement C1q and C5b-9 proteins and appeared degenerative. Furthermore, D-related human leukocyte antigen (HLA-DR)–positive fibers of reactive microglia were spatially closer (p < 0.001) and often in contact with the Ig-positive neurons than the Ig-negative neurons. Collectively, these data suggest that the Ig-positive neurons detected in AD brains are dying from the processes of the antibody-induced classical complement pathway.

Keywords

Alzheimer's disease autoimmune disease complement classical pathway immunoglobulin C1q C5b-9 immunohistochemistry neurodegeneration

References

D'Andrea MR : Evidence linking neuronal cell death to autoimmunity in Alzheimer's disease. Brain Res. 2003; 982: 19-30.

D'Andrea MR : Add Alzheimer's disease to the list of autoimmune diseases. Med Hypotheses. 2005; 64(3): 458-463.

Emmerling MR , Watson MD , Ruby CA , et al.: The role of complement in Alzheimer's disease pathology. Biochem Biophys Acta. 2000; 1502: 158-171.

Webster S , Lue LF , Brachova L , et al.: Molecular and cellular characterization in the membrane attack complex, C5b-9, in Alzheimer's disease. Neurobiol Aging. 1997; 18: 415-421.

D'Andrea MR , Nagele RG , Wang H-Y , et al.: Evidence that neurons accumulating amyloid can undergo lysis to form amyloid plaques in Alzheimer's disease. Histopathology. 2001; 38: 120-134.

D'Andrea MR , Reiser PA , Gumula NA , et al.: Application of triple-label immunohistochemistry to characterize inflammation in Alzheimer's disease brains. Biotech Histochem. 2001; 76: 97-106.

Fonseca MI , Zhou J , Botto M , et al.: Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer's disease. J Neurosci. 2004; 24(29): 6457-6465.

Wang HY , Lee DHS , D'Andrea MR , et al.: ß-amyloid1-42 binds to a7 nicotinic acetylcholine receptor with high affinity: Implications for Alzheimer's disease pathology. J Biol Chem. 2000; 275(8): 5626-5632.

Weerth SH , Rus H , Shin ML , et al.: Complement C5 in experimental autoimmune encephalomyelitis (EAE) facilitates remyelination and prevents gliosis. Am J Pathol. 2003; 163(3): 1069-1080.

10.

Pasinetti GM : Inflammatory mechanisms in neurodegeneration and Alzheimer's disease: The role of the complement system. Neurobiol Aging. 1996; 17(5): 707-716.

11.

Rogers J , Cooper NR , Schultz J , et al.: Complement activation by ß-amyloid in Alzheimer's disease. Proc Natl Acad Sci USA. 1992; 89: 10016-10020.

12.

Loeffler DA , Camp DM , Schonberger MB , et al.: Early complement activation increases in the brain in some aged normal subjects. Neurobiol Aging. 2004; 25(8): 1001-1007.

13.

Shen Y , Lue L-F , Yang L-B , et al.: Complement activation by neurofibrillary tangles in Alzheimer's disease. Neurosci Lett. 2001; 305: 165-168.

14.

Singhrao SK , Neal JW , Morgan BP , et al.: Increased complement biosynthesis by microglia and complement activation on neurons in Huntington's disease. Exp Neurol. 1999; 159: 362-376.

15.

Barnum SR : Complement biosynthesis in the central nervous system. Crit Rev Oral Biol Med. 1995; 6: 132-146.

16.

Mukherjee P , Pasinetti GM : The role of complement anaphylatoxin C5a in neurodegeneration: Implications in Alzheimer's disease. J Neuroimmunol. 2000; 105: 124-130.

17.

Korb LC , Ahearn JM : C1q binding directly and specifically to surface belbs of aopototic human keratinocytes. J Immunol. 1997; 158: 4525-4528.

18.

Webster SD , Yang AJ , Margol L , et al.: Complement component C1q modulates the phagocytic behavior of microglia. Exp Neurol. 2000; 161: 127-138.

19.

Neuroinflammation Working Group : Inflammation and Alzheimer's disease. Neurobiol Aging. 2000; 21: 383-421.

20.

Piddlesden SJ , Lassmann H , Zimprich F , et al.: The demyelinating potential of autoantibodies to myelin oligodendrocyte glycoprotein is related to their ability to fix complement. Am J Pathol. 1993; 143(2): 555-564.

21.

Velazquez P , Cribbs DH , Poulos TL , et al.: Aspartate residue 7 in amyloid ß-protein is critical for classical complement pathway activation: Implications for Alzheimer's disease pathogenesis. Nat Med. 1997; 3(1): 77-79.

22.

Spiegel K , Barnum SR , Emmerling ML . In Wood PL (ed.): Neuroinflammation: Mechanisms and Management. Totowa, NJ: Humana Press, 1997: 129-176.

23.

D'Andrea MR , Cole GM , Ard MD : The microglial phagocytic role with specific plaque types in the Alzheimer disease brain. Neurobiol Aging. 2004; 25(5): 675-683.