Affiliation:
1. Macquarie University FMHS: Macquarie University Faculty of Medicine and Health Sciences
2. MUSC: Medical University of South Carolina
3. DZNE e V: Deutsches Zentrum fur Neurodegenerative Erkrankungen eV
4. Harvard Medical School Department of Medicine
5. Macquarie University
Abstract
Abstract
Background. Amyloid-β (Aβ) and tau form
pathogenic lesions in Alzheimer’s disease (AD) brains. As ΑD
clinically progresses, tau pathology propagates in a very distinct
pattern between connected brain areas. The molecular mechanisms
underlying this tau pathology spread remain largely unknown.
Genome-wide association studies have identified polymorphisms in
triggering receptor expressed on myeloid cells 2
(TREM2) as genetic risk factors for AD and regulators of
Aβ pathology-dependent tau propagation. Whether TREM2 contributes
to neuron-to-neuron spreading of pathological tau remains
unknown.
Methods. Here, we crossed Trem2-deficient
mice with P301S tau transgenic TAU58 mice and subjected the mice to
behavioural testing and assessed neuropathology. Microglial
activation states were determined using cytometry by time of flight
(CyTOF) and quantitative PCR. Tau spreading was assessed in
vivo using tracing of focal tau expression.
Results. Trem2 depletion significantly
aggravated tau-induced early-onset motor and behavioural deficits.
Neuropathologically, Trem2 reduction increased the number
of hyperphosphorylated tau lesions in young TAU58 brains and
reduced disease-associated microglia. Direct assessment of
inter-neuronal spread of tau in vivo revealed
significantly enhanced propagation of tau in the absence of
Trem2, suggesting that microglial TREM2 limits the
progression of tau pathology in disease.
Conclusion. Taken together, our data suggests that
reduced TREM2 function accelerates the onset and progression of
functional deficits and tau neuropathology in tau transgenic mice,
which might –at least in part– be due to increased tau spreading.
Therefore, reduced TREM2 function may contribute to early AD by
augmenting tau toxicity and its inter-neuronal propagation.
Publisher
Research Square Platform LLC
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