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1. LRRK2 kinase inhibition reverses G2019S mutation-dependent effects on tau pathology progression

   https://doi.org/10.1186/s40035-024-00403-2  

   Lubben, Noah ; Brynildsen, Julia K. ; Webb, Connor M. ; Li, Howard L. ; Leyns, Cheryl E. G. ; Changolkar, Lakshmi ; Zhang, Bin ; Meymand, Emily S. ; O’Reilly, Mia ; Madaj, Zach ; et al ( March 2024 , Translational Neurodegeneration)

   Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson’s disease (PD). These mutations elevate the LRRK2 kinase activity, making LRRK2 kinase inhibitors an attractive therapeutic. LRRK2 kinase activity has been consistently linked to specific cell signaling pathways, mostly related to organelle trafficking and homeostasis, but its relationship to PD pathogenesis has been more difficult to define.LRRK2-PD patients consistently present with loss of dopaminergic neurons in the substantia nigra but show variable development of Lewy body or tau tangle pathology. Animal models carryingLRRK2mutations do not develop robust PD-related phenotypes spontaneously, hampering the assessment of the efficacy of LRRK2 inhibitors against disease processes. We hypothesized that mutations inLRRK2may not be directly related to a single disease pathway, but instead may elevate the susceptibility to multiple disease processes, depending on the disease trigger. To test this hypothesis, we have previously evaluated progression of α-synuclein and tau pathologies following injection of proteopathic seeds. We demonstrated that transgenic mice overexpressing mutant LRRK2 show alterations in the brain-wide progression of pathology, especially at older ages.

   Here, we assess tau pathology progression in relation to long-term LRRK2 kinase inhibition. Wild-type or LRRK2^G2019Sknock-in mice were injected with tau fibrils and treated with control diet or diet containing LRRK2 kinase inhibitor MLi-2 targeting the IC50 or IC90 of LRRK2 for 3–6 months. Mice were evaluated for tau pathology by brain-wide quantitative pathology in 844 brain regions and subsequent linear diffusion modeling of progression.

   Consistent with our previous work, we found systemic alterations in the progression of tau pathology in LRRK2^G2019Smice, which were most pronounced at 6 months. Importantly, LRRK2 kinase inhibition reversed these effects in LRRK2^G2019Smice, but had minimal effect in wild-type mice, suggesting that LRRK2 kinase inhibition is likely to reverse specific disease processes in G2019S mutation carriers. Additional work may be necessary to determine the potential effect in non-carriers.

   This work supports a protective role of LRRK2 kinase inhibition in G2019S carriers and provides a rational workflow for systematic evaluation of brain-wide phenotypes in therapeutic development.

    

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2. Distinct Patterns of Hippocampal Pathology in Alzheimer's Disease with Transactive Response DNA‐binding Protein 43

   https://doi.org/10.1002/ana.26762  

   Minogue, Grace ; Kawles, Allegra ; Zouridakis, Antonia ; Keszycki, Rachel ; Macomber, Alyssa ; Lubbat, Vivienne ; Gill, Nathan ; Mao, Qinwen ; Flanagan, Margaret E. ; Zhang, Hui ; et al ( September 2023 , Annals of Neurology)

   Age‐related dementia syndromes are often not related to a single pathophysiological process, leading to multiple neuropathologies found at autopsy. An amnestic dementia syndrome can be associated with Alzheimer's disease (AD) with comorbid transactive response DNA‐binding protein 43 (TDP‐43) pathology (AD/TDP). Here, we investigated neuronal integrity and pathological burden of TDP‐43 and tau, along the well‐charted trisynaptic hippocampal circuit (dentate gyrus [DG], CA3, and CA1) in participants with amnestic dementia due to AD/TDP, amnestic dementia due to AD alone, or non‐amnestic dementia due to TDP‐43 proteinopathy associated with frontotemporal lobar degeneration (FTLD‐TDP).

   A total of 48 extensively characterized cases (14 AD, 16 AD/TDP, 18 FTLD‐TDP) were analyzed using digital HALO software (Indica Labs, Albuquerque, NM, USA) to quantify pathological burden and neuronal loss.

   In AD/TDP and FTLD‐TDP, TDP‐43 immunoreactivity was greatest in the DG. Tau immunoreactivity was significantly greater in DG and CA3 in AD/TDP compared with pure AD. All clinical groups showed the highest amounts of neurons in DG, followed by CA3, then CA1. The AD and AD/TDP groups showed lower neuronal counts compared with the FTLD‐TDP group across all hippocampal subregions consistent with the salience of the amnestic phenotype.

   We conclude that AD/TDP can be distinguished from AD and FTLD‐TDP based on differential regional distributions of hippocampal tau and TDP‐43. Findings suggest that tau aggregation in AD/TDP might be enhanced by TDP‐43. ANN NEUROL 2023;94:1036–1047

    

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3. The Membrane Axis of Alzheimer's Nanomedicine

   https://doi.org/10.1002/anbr.202000040  

   Li, Yuhuan ; Tang, Huayuan ; Andrikopoulos, Nicholas ; Javed, Ibrahim ; Cecchetto, Luca ; Nandakumar, Aparna ; Kakinen, Aleksandr ; Davis, Thomas P. ; Ding, Feng ; Ke, Pu Chun ( December 2020 , Advanced NanoBiomed Research)

   Alzheimer's disease (AD) is a major neurological disorder impairing its carrier's cognitive function, memory, and lifespan. While the development of AD nanomedicine is still nascent, the field is evolving into a new scientific frontier driven by the diverse physicochemical properties and theranostic potential of nanomaterials and nanocomposites. Characteristic to the AD pathology is the deposition of amyloid plaques and tangles of amyloid beta (Aβ) and tau, whose aggregation kinetics may be curbed by nanoparticle inhibitors via sequence‐specific targeting or nonspecific interactions with the amyloidogenic proteins. As literature implicates cell membrane as a culprit in AD pathogenesis, herein, the membrane axis of AD nanomedicine is summarized and a new rationale that the field development may greatly benefit from harnessing our existing knowledge of Aβ‐membrane interaction, nanoparticle–membrane interaction, and Aβ–nanoparticle interaction is presented.

    

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4. Alzheimer’s-like pathology in aging rhesus macaques: Unique opportunity to study the etiology and treatment of Alzheimer’s disease

   https://doi.org/10.1073/pnas.1903671116  

   Arnsten, Amy F. T. ; Datta, Dibyadeep ; Leslie, Shannon ; Yang, Sheng-Tao ; Wang, Min ; Nairn, Angus C. ( December 2019 , Proceedings of the National Academy of Sciences)

   Although mouse models of Alzheimer’s disease (AD) have provided tremendous breakthroughs, the etiology of later onset AD remains unknown. In particular, tau pathology in the association cortex is poorly replicated in mouse models. Aging rhesus monkeys naturally develop cognitive deficits, amyloid plaques, and the same qualitative pattern and sequence of tau pathology as humans, with tangles in the oldest animals. Thus, aging rhesus monkeys can play a key role in AD research. For example, aging monkeys can help reveal how synapses in the prefrontal association cortex are uniquely regulated compared to the primary sensory cortex in ways that render them vulnerable to calcium dysregulation and tau phosphorylation, resulting in the selective localization of tau pathology observed in AD. The ability to assay early tau phosphorylation states and perform high-quality immunoelectron microscopy in monkeys is a great advantage, as one can capture early-stage degeneration as it naturally occurs in situ. Our immunoelectron microscopy studies show that phosphorylated tau can induce an “endosomal traffic jam” that drives amyloid precursor protein cleavage to amyloid-β in endosomes. As amyloid-β increases tau phosphorylation, this creates a vicious cycle where varied precipitating factors all lead to a similar phenotype. These data may help explain why circuits with aggressive tau pathology (e.g., entorhinal cortex) may degenerate prior to producing significant amyloid pathology. Aging monkeys therefore can play an important role in identifying and testing potential therapeutics to protect the association cortex, including preventive therapies that are challenging to test in humans.

    

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5. JEDI: J oint E stimation D iffusion I maging of macroscopic and microscopic tissue properties

   https://doi.org/10.1002/mrm.28141  

   Frank, Lawrence R. ; Zahneisen, Benjamin ; Galinsky, Vitaly L. ( January 2020 , Magnetic Resonance in Medicine)

   A new method for enhancing the sensitivity of diffusion MRI (dMRI) by combining the data from single (sPFG) and double (dPFG) pulsed field gradient experiments is presented.

   This method uses our JESTER framework to combine microscopic anisotropy information from dFPG experiments using a new method called diffusion tensor subspace imaging (DiTSI) to augment the macroscopic anisotropy information from sPFG data analyzed using our guided by entropy spectrum pathways method. This new method, called joint estimation diffusion imaging (JEDI), combines the sensitivity to macroscopic diffusion anisotropy of sPFG with the sensitivity to microscopic diffusion anisotropy of dPFG methods.

   Its ability to produce significantly more detailed anisotropy maps and more complete fiber tracts than existing methods within both brain white matter (WM) and gray matter (GM) is demonstrated on normal human subjects on data collected using a novel fast, robust, and clinically feasible sPFG/dPFG acquisition.

   The potential utility of this method is suggested by an initial demonstration of its ability to mitigate the problem of gyral bias. The capability of more completely characterizing the tissue structure and connectivity throughout the entire brain has broad implications for the utility and scope of dMRI in a wide range of research and clinical applications.

    

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