TARGET - INTEGRAL MEMBRANE PROTEIN FUNCTION: DIRECTING NEURAL STEM CELL FATE AND TARGETING LIPID SIGNALLING PATHWAYS

RESEARCH DISCIPLINES: BIOCHEMISTRY, NEUROSCIENCE, PHARMACOLOGY, CELL BIOLOGY, MOLECULAR BIOLOGY; RESEARCH AREAS: NEURODEGENERATIVE DISEASES (ALZHEIMER'S DISEASE, PARKINSON'S DISEASE, EPILEPSY), ADULT NEURAL STEM CELLS, PLASTICITY AND NEUROREGENERATION, HORMONAL REGULATION, LIPIDOMICS, SUPER-RESOLUTION MICROSCOPY
Figure1

Neuroregeneration: Clinical trials hint at the potential of stem cell replacement strategies as stroke therapy yet longitudinal studies are conspicuous in their absence. Experimental evidence warns that activation of resident neural stem and progenitor cells (NPCs) in injured tissue can result in the integration of inappropriate cell types into damaged circuits causing further neurological complications. Attention must also be paid to the possibility that tumour stem cells can arise from the transformation of NPC populations in diseased tissue. Clearly, validation of cell replacement strategies will depend upon a comprehensive understanding of how appropriate cell lineages are effectively generated in injured brain.

Neurodegeneration: Two central pathologies define Alzheimer's Disease (AD): (1) intraneuronal accumulation of neurofibrillary tangles composed of hyperphosphorylated tau and (2) aberrant processing of the amyloid precursor protein (APP) to toxic amyloid beta (Abeta fragments. The most damaging is Abeta42. Accumulation is gradual with assembly of soluble Abeta oligomers impairing synaptic function and signalling synaptic loss The 'amyloid hypothesis' defines these events as the root cause of AD. Yet, despite strong proofs that Abeta and tau aggregations are driving pathologies, converging evidence suggests that they likely represent only two of multiple determinants necessary for AD memory impairment. This refinement is based on evidence that Abeta42 accumulation (at AD load levels) can be found in cognitively 'normal' elderly as well as humanized mouse models of Abeta42/tau accumulation with little manifestation of memory deficits. These observations have prompted a 're-imagining' of the amyloid hypothesis (Karl Herrup). Here, the amyloid deposition cycle, aggravated by chronic neuroinflammation, triggers a critical 'change in state'. This 'change of state' is envisioned as a convergence of metabolic disruptions that result in "a new 'normal' biology primed towards neurodegeneration and dementia". Targeting these metabolic determinants represents a novel, potentially transformative, approach to prevent AD conversion.

Notable contribution

Granger MW, Franko B, Taylor MW, Messier C, St George-Hyslop P, Bennett SAL (2016) A TgCRND8 mouse model of Alzheimer's disease exhibits sexual dimorphisms in behavioral indices of cognitive reserve, J Alz Dis, 51:757-773 doi: 10.3233/JAD-150587

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Funding

CIHR - Aberrant phospholipid and sphingolipid metabolism is a primary and targetable pathology in Alzheimer Disease (with PI: Dr Steffany Bennett, Co-invest: Dr Daniel Figeys, Dr Kristin Baetz, Dr William Stanford, Dr Sandra Black)

CIHR - Targeting connexin and pannexin communication in demyelinating diseases (with Co-Invest: Dr John Arnason, Dr Eve Tsai)

Canadian Rare Diseases: Models and Mechanisms Network - Phenotypic and biochemical characterization of a CRISPR/Cas murine model of neonatal progeroid syndrome (with Co-Invest: Dr David Dyment)

University of Ottawa-Shanghai Jiao Tong University School of Medicine Joint Medical Research Funding Competition - Membrane metabolism and tau hyperphosporylation in AD transgenics (with Co-PI: Dr Weidong Le)