In VivoPositron Emission Tomographic Imaging of Glial Responses to Amyloid-β and Tau Pathologies in Mouse Models of Alzheimer's Disease and Related Disorders

Abstract

Core pathologies of Alzheimer's disease (AD) are aggregated amyloid-β peptides (Aβ) and tau, and the latter is also characteristic of diverse neurodegenerative tauopathies. These amyloid lesions provoke microglial activation, and recent neuroimaging technologies have enabled visualization of this response in living brains using radioligands for the peripheral benzodiazepine receptor also known as the 18-kDa translocator protein (TSPO). Here we elucidated contributions of Aβ and tau deposits to in vivo TSPO signals in pursuit of mechanistic and diagnostic significance of TSPO imaging in AD and other tauopathies. A new antibody to human TSPO revealed induction of TSPO-positive microgliosis by tau fibrils in tauopathy brains. Emergence of TSPO signals prior to occurrence of brain atrophy and thioflavin-S-positive tau amyloidosis was also demonstrated in living mice transgenic for mutant tau by positron emission tomography (PET) with two classes of TSPO radioligands, [11C]AC-5216 and [18F]fluoroethoxy-DAA1106. Meanwhile, only modest TSPO elevation was observed in aged mice modeling Aβ plaque deposition, despite the notably enhanced in vivo binding of amyloid radiotracer, [11C]Pittsburgh Compound-B, to plaques. In these animals, [11C]AC-5216 yielded better TSPO contrasts than [18F]fluoroethoxy-DAA1106, supporting the possibility of capturing early neurotoxicity with high-performance TSPO probes. Furthermore, an additional line of mice modeling intraneuronal Aβ accumulation displayed elevated TSPO signals following noticeable neuronal loss, unlike TSPO upregulation heralding massive neuronal death in tauopathy model mice. Our data corroborate the utility of TSPO-PET imaging as a biomarker for tau-triggered toxicity, and as a complement to amyloid scans for diagnostic assessment of tauopathies with and without Aβ pathologies.

Pyroglutamate-Modified Amyloid-β Protein Demonstrates Similar Properties in an Alzheimer's Disease Familial Mutant Knock-In Mouse and Alzheimer's Disease Brain

“…This low level of pE3Aβ in Tg2576 is consistent with previous reports [38], and is similar to the fraction found in the brain of related models of APP overexpression, e.g. the PDAPP model [39,40], where only 0.65% of total Aβ has a pE3Aβ N-terminus. While histological plaque quantification was not performed in the present study, a previous report [24] demonstrated a cortical plaque burden of 10% in 18-month Tg2576 and only 3% in 18-month APP/PS1-dKI.…”

Longitudinal Assessment of Cerebral β-Amyloid Deposition in Mice Overexpressing Swedish Mutant β-Amyloid Precursor Protein Using 18F-Florbetaben PET

“…6). In any event, white matter contributions will tend to cancel out in SUVR and BP ND calculations, a contention supported by the absolute lack of any spurious cortical signal in WT animals and young transgenic animals-that is, SUVR is 1 and BP ND is 0, as likewise reported in earlier reports with 11 C-PIB (8,34). This lack of bias in baseline estimates of b-amyloid deposition allows us to estimate the sensitivity of our method for detecting b-amyloid to be approximately 1.5% plaque load (derived from Fig.…”

Reactive Glia not only Associates with Plaques but also Parallels Tangles in Alzheimer's Disease

“…Novel radioligands targeting the same receptor in microglia have recently proven to track considerably better with -induced neurodegeneration in mice overexpressing mutant human than with amyloid burden in animals modeling A␤ plaque deposition. 39 If glial responses become partially independent from amyloid plaques and their contribution to neurodegeneration is relevant, then removal of amyloid plaques with anti-A␤-directed therapies, such as passive or active immunization, might not be sufficient to block this neurotoxicity. In this scenario, the transient microglial response triggered by anti-A␤ immunization might have deleterious effects on the neuropil, even though there is an overall decrease in gliosis on clearance of amyloid plaques.…”