Alzheimer's & Dementia最新文献

Background

Alzheimer’s disease is a neurodegenerative disease that affects patients’ ability to perform activities of daily living thus requiring assistance from their loved ones. The progressive nature of the disease unravels new and continuous challenges for the caregivers posing a huge burden on caregiving. However, there is little research in Sub- Saharan African countries including Kenya, on caregiver’s experiences managing patients with Alzheimer’s disease. We conducted an ethnographic study at the Aga Khan University Hospital (AKUH) to understand caregivers’ experiences and practices caring for patients with Alzheimer’s disease.

Methods

We purposively recruited 30 caregivers who have been managing patients with Alzheimer’s disease from the Neurology clinic at AKUH. We conducted semi-structured in- depth interviews in English or Swahili, which lasted for about 60 minutes to completion. Interviews were audio-recorded, transcribed, and analyzed thematically with the aid of Nvivo-12 software.

Results

Key themes identified from data included: (a) Caregiver knowledge and skills in managing patients (b) Caregiving burden (emotional, psychological, physical, financial) (c) dealing with patient’s changing personality, moods, and loss of self-identity (d) fulfilment and privilege taking care of loved ones (e) navigating through self-chores and caregiving roles. Overall, most caregivers lacked knowledge and skills for managing patients with Alzheimer’s. Given the limited resources, awareness and support of Alzheimer’s in Kenya, we found that caregivers carried the burden of taking care of their loved ones with some reporting mental health issues related to caregiving burden. In addition, lack of skills and training on how to manage patients’ changing personalities and patients’ loss of identity left many caregivers frustrated and worn out. Despite the challenges, caregivers had a sense of fulfilment taking care of their loved ones.

Conclusion

Caregivers of Alzheimer’s disease in Kenya require support from healthcare providers and other stakeholders in terms of trainings and capacity building skills to enable them to provide optimal care for the patients. They also require psychosocial support to maintain a healthy balance between their daily life activities and those of caregiving.

Background

Tau proteins aggregate in a number of neurodegenerative disorders known as tauopathies. Various studies have highlighted the role of microtubule-binding domains in the intracellular aggregation of Tau protein.

Method

Using a library of synthetic VHHs humanized in collaboration with Hybrigenics, we have developed a number of anti-tau VHHs. We use a combination of biophysical and biochemical methods, cell-based assays, viral vectors and tau transgenic mice to explore the ability of these VHHs to target intracellular tau protein.

Result

A dozen anti-tau VHHs were obtained near and in microtubule-binding regions. After screening and optimization, three of them (F8-2, H3-2 and Z70) were selected for further studies and AAV vector delivery to tau transgenic mice. Biochemical characterization of F8-2 has already been published [1]. VHH Z70 targeting the PHF6 epitope has already demonstrated its ability to reduce tau seeding in cellular FRET assays and by lentiviral vectorization in animals [2]. Here, using AAV vectors, we demonstrate its safety in wild-type mice and its efficacy in tau transgenic mice. VHH H3-2 has a unique mode of action which will be discussed.

Conclusion

In our tau pipeline, we have developed innovative new therapeutic tools, which are at various stages of development for preclinical validation.

References

[1] Danis C, et al. (2022) Inhibition of Tau seeding by targeting Tau nucleation core within neurons with a single domain antibody fragment. Mol Ther, 30(4):1484-1499

[2] Dupré E, et al. (2019) Single chain antibody fragments as new tools for studying the neuronal Tau protein physiopathology. ACS Chemical Neurosci, 10(9):3997-4006

Background

The initiation of amyloid plaque deposition signifies a crucial stage in Alzheimer’s disease (AD) progression, which often coincides with the disruption of neural circuits and cognitive decline. While the role of excitatory-inhibitory balance is increasingly recognized in AD pathophysiology, targeted therapies to modulate this balance remain underexplored. This study investigates the effect of perampanel, a selective non-competitive AMPA receptor antagonist, in modulating neurophysiological changes in hAPP-J20 transgenic Alzheimer’s mice.

Method

Perampanel was administered to hAPP-J20 mice and their age-matched wildtype littermates, aged 20-25 weeks, during the critical amyloid plaque deposition period in the hippocampus. We continuously monitored the local field potential of the hippocampal CA1 region using long-term wireless telemetry (sampled at a rate of 2 kHz), capable of calculating rates of high-frequency oscillations (HFOs) to gauge potential epileptiform activity. To evaluate cognitive function, Morris water maze test was conducted. Glutamatergic pyramidal cells and GABAergic interneurons was quantified to assess neuronal health, and the hippocampal concentration of neuropeptide Y (NPY) was measured as an indirect indicator of mossy fiber sprouting.

Result

Treatment with perampanel resulted in a significant rescue of GABAergic interneuron depletion and reduced the pathological increase of HFOs, indicative of restored excitatory-inhibitory balance. In line with the restored excitatory-inhibitory balance, it also attenuated neuronal sprouting labeled by NPY. Additionally, perampanel administration led to a substantial decrease in amyloid plaque accumulation in the hippocampus, though the observed memory deficit in transgenic mice did not change significantly.

Conclusion

Our findings reveal that perampanel, an established antiseizure medication, exerts multifaceted neuroprotective effects in the AD mouse model. The preservation of interneurons, reduction of pathological neural hyperactivity, and decreased amyloid plaque burden highlighted the potential of targeting glutamatergic pathways as a therapeutic strategy. The study warrants further investigation of perampanel as a promising candidate for ameliorating the pathophysiological and cognitive deficits associated with AD.