Increased Transforming Growth Factor β2 in the Neocortex of Alzheimer's Disease and Dementia with Lewy Bodies is Correlated with Disease Severity and Soluble Aβ42 Load

Background: Of the three transforming growth factor (TGF)-beta isoforms known, TGF beta 1 deficits have been widely reported in Alzheimer's disease (AD) and studied as a potential therapeutic target. In contrast, the status of TGF beta 2, which has been shown to mediate amyloid-beta (A beta)-mediated neuronal death, are unclear both in AD and in Lewy body dementias (LBD) with differential neuritic plaque and neurofibrillary tangle burden. Objective: To measure neocortical TGF beta 2 levels and their correlations with neuropathological and clinical markers of disease severity in a well-characterized cohort of AD as well as two clinical subtypes of LBD, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), known to manifest relatively high and low A beta plaque burden, respectively. Methods: Postmortem samples from temporal cortex (BA21) were measured for TGF beta 2 using a Luminex-based platform, and correlated with scores for neuritic plaques, neurofibrillary tangles, alpha -synuclein pathology, dementia severity (as measured by annual decline of Mini-Mental State Examination scores) as well as soluble and total fractions of brain A beta(42). Results: TGF beta 2 was significantly increased in AD and DLB, but not in PDD. TGF beta 2 also correlated with scores for neurofibrillary tangles, Lewy bodies (within the LBD group), dementia severity, and soluble A beta(42) concentration, but not with neuritic plaque scores, total A beta(42), or monomeric alpha-synuclein immunoreactivity. Conclusions: TGF beta 2 is increased in the temporal cortex of AD and DLB, and its correlations with neuropathological and clinical markers of disease severity as well as with soluble A beta(42) load suggest a potential pathogenic role in mediating the neurotoxicity of non-fibrillar A beta. Our study also indicates the potential utility of targeting TGF beta 2 in pharmacotherapeutic approaches to AD and DLB.