Alzheimer's disease neurofibrillary degeneration: pivotal and multifactorial.
Independent of the aetiology, AD (Alzheimer's disease) neurofibrillary degeneration of abnormally hyperphosphorylated tau, a hallmark of AD and related tauopathies, is apparently required for the clinical expression of the disease and hence is a major therapeutic target for drug development. However, AD is multifactorial and heterogeneous and probably involves several different aetiopathogenic mechanisms. On the basis of CSF (cerebrospinal fluid) levels of Abeta(1-42) (where Abeta is amyloid beta-peptide), tau and ubiquitin, five different subgroups, each with its own clinical profile, have been identified. A successful development of rational therapeutic disease-modifying drugs for AD will require understanding of the different aetiopathogenic mechanisms involved and stratification of AD patients by different disease subgroups in clinical trials. We have identified a novel aetiopathogenic mechanism of AD which is initiated by the cleavage of SET, also known as inhibitor-2 (I(2)(PP2A)) of PP2A (protein phosphatase 2A) at Asn(175) into N-terminal (I(2NTF)) and C-terminal (I(2CTF)) halves and their translocation from the neuronal nucleus to the cytoplasm. AAV1 (adeno-associated virus 1)-induced expression of I(2CTF) in rat brain induces inhibition of PP2A activity, abnormal hyperphosphorylation of tau, neurodegeneration and cognitive impairment in rats. Restoration of PP2A activity by inhibition of the cleavage of I(2)(PP2A)/SET offers a promising therapeutic opportunity in AD with this aetiopathogenic mechanism.
Iqbal
Khalid
K
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York, NY 10314, USA. khalid.iqbal.ibr@gmail.com
Wang
Xiaochuan
X
Blanchard
Julie
J
Liu
Fei
F
Gong
Cheng-Xin
CX
Grundke-Iqbal
Inge
I
D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D003704:Dementia / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008954:Models, Biological; D009410:Nerve Degeneration / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000378:metabolism* / Q000473:pathology / Q000502:physiology*; D051381:Rats; D024801:Tauopathies / Q000209:etiology / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism / Q000502:physiology
D016875:tau Proteins