TNF and Alzheimer's

Tarkowski E, Andreasen N, Tarkowski A, Blennow K Intrathecal inflammation precedes development of Alzheimer's disease. [Comparative Study, Journal Article, Research Support, Non-U.S. Gov't] J Neurol Neurosurg Psychiatry 2003 Sep; 74(9):1200-5.

OBJECTIVES: To analyse the cerebrospinal fluid (CSF) values of the proinflammatory cytokines, interleukin 1beta (IL1beta), tumour necrosis factor alpha (TNFalpha), GM-CSF, of the anti-inflammatory cytokine TGFbeta, of tau protein, a marker for neurodegeneration, and of beta amyloid (Abeta), a protein involved in the formation of senile plaques, in prospectively followed up patients with mild cognitive impairment (MCI).

METHODS: Analyses of CSF levels of TNFalpha, IL1beta, GM-CSF, TGFbeta, betaa, and tau protein were performed using ELISA in 56 patients with MCI who were followed up prospectively and in 25 age matched, healthy controls.

RESULTS: Patients with MCI displayed significantly higher levels of TNFalpha and tau protein and significantly lower levels of TGFbeta and Abeta compared with the healthy controls. After nine months of follow up, 25 patients still displayed MCI while the remaining 31 patients had progressed to Alzheimer's disease (AD). Only MCI patients who progressed to AD at follow up, showed significantly higher CSF levels of TNFalpha than controls. In addition, reduced CSF-Abeta42 levels were only found in MCI patients that progressed to AD, further supporting the notion that disturbed metabolism of Abeta is an early finding in AD.

CONCLUSIONS: These results demonstrate increased production of the proinflammatory cytokine, TNFalpha and decreased production of the anti-inflammatory cytokine TGFbeta in patients with MCI at risk to develop AD, suggesting a propensity towards inflammation in this patient group and indicating that CNS inflammation is a early hallmark in the pathogenesis of AD.

Tarkowski E, Liljeroth AM, Minthon L, Tarkowski A, Wallin A, Blennow K Cerebral pattern of pro- and anti-inflammatory cytokines in dementias. [Journal Article, Review]
Brain Res Bull 2003 Aug 15; 61(3):255-60.

The knowledge regarding putative inflammatory component(s) participating in Alzheimer's disease (AD) and vascular dementia (VAD) is scarce. Recently, we have demonstrated the presence of certain inflammatory cytokines in the cerebrospinal fluid (CSF) of demented patients. Although the initial event(s) triggering the neurodegenerative processes in AD versus VAD may be different and lead to different neuropathological changes, it may initiate a similar cascade of cytokine production in response to neuronal injury. The cytokines released in the central nervous system (CNS) may, in turn, act in a similar manner in both diseases, amplifying some pathological changes such as amyloidogenesis and white matter lesions or on the contrary acting as neuroprotective molecules. This review will focus on the intracerebral production of the pro- and anti-inflammatory cytokines interleukin IL-1beta, IL-1 receptor antagonist (IL-1ra), IL-6 and TNF-alpha in dementia, and their relation to gene polymorphism, to cerebral neuronal damage, apoptosis, and to clinical variables of dementia. Our results, which show for the first time strikingly increased CSF levels of TNF-alpha but not of TNF-beta, IL-1beta or IL-6 in AD and VAD, may form a conceptual framework for further studies of neuroprotective mechanisms in dementias.

Perry RT, Collins JS, Wiener H, Acton R, Go RC The role of TNF and its receptors in Alzheimer's disease. [Journal Article, Review] Neurobiol Aging 2001 Nov-Dec; 22(6):873-83.

Tumor necrosis factor (TNF) is an important proinflammatory cytokine that is upregulated in Alzheimer disease (AD) patients and involved with AD genes. Several TNF promoter polymorphisms that increase expression are associated with inflammatory and infectious diseases. We previously reported results that detected a AD associated region near the TNF gene. Using family-based association tests we also reported an association between AD and a TNF haplotype in sibling-pair families, and a significant increase in the mean age of onset for a group of African-American AD patients carrying this same haplotype. Previous reports have shown that that the chromosome 1p and chromosome 12p regions are linked to late-onset AD. These two regions harbor TNF receptors (TNFR) 2 and 1, respectively, and binding to them mediates biological effects of TNF. We found a significant asssociation of a TNFR2 exon 6 polymorphism with late-onset AD in families with no individuals possessing the APOE E4E4 genotype under a dominant model. We found no significant association of three polymorphisms in the TNFR1 gene to AD. These results provide further evidence for the involvement of TNF in the pathogenesis of AD.