Alzheimers Disease

Symptoms Acquired Global impairment Memory impairment consisting of at least one of the following: Aphasia (language) Apraxia (learned movement) Agnosia (recognition)

Histopathology Senile plaques (Ab) Neurofibrillary tangles (Tau) Neurone loss Pyramidal Neuron loss Dendritic loss Amyloid Beta deposits show up in PET scan Loss of hippocampus shows up in MRI

Genetic Contributions Chromosome 21 APP Chromosome 14 (PS1) Chromosome 1 (PS2)

Presenilin are a family of multipass transmembrane proteins that function as part of a gamma-secretase protease complex! Gamma and beta secretase enzymes are needed to cleave APP down to Amyloid gamma secretase favours breakdown into Ab42 Ab42 is most likely to aggregate

Apolipoprotein E (APOE) genotype E4 variant is the only unequivocal genetic risk factor for late onset AD Studies suggest that APOE enhances the proteolytic breakdown of Amyloid beta E4 expression reduces efficiency of breakdown as E4 is inefficient at AB breakdown! Thus vulnerability to AD

Drug Targets Are based on 3 aims: Symptomatic relief o Cognitive symptoms o Behavioural symptoms Disease slowing modification strategies Disease prevention

Symptomatic Relief Cholinergic 5HT Glutamate

Cholinergic (associated with memory loss) Changes detected in AD include: Cholinergic acetyltrasferase activity reduced (makes Ach from choline and acetyl COA) Reduced muscarinic ACH binding

Treatment Cholinesterase inhibitors to inhibit Ach breakdown! o Improve cognitive function but cannot reduce or reverse degeneration!

Glutamate Involved in cognition Disrupted in AD Sustained low level activation of glutamate receptors (NMDA) background noise Due to impairments in NMDA function and Glutamine cycle in AD

Disruption of vGLUT inhibits transport of glutamate into vesicles thus only low level glutamate released Damaged reuptake protein in the astroglia also contribute to the accumulation of glutamate in the synapse **background noise impairs recognition of neurotransmitter signal and mediates glutamate excitoxicity!**

Pharmacology of AD D cycloserine is a NMDA partial agonist o shows improvement in cognition in AD AMPA kinases o Modulate glutamate action on AMPA receptors causing influx of Na+ activating NMDA cells via Mg2+ displacement o Shows increase in cognitive function! Memantine is a non-competitive, voltage operated NMDA antagonist of moderate affinity (like Mg2+) o In AD brain, disturbed glutamate levels cause partial activation of NMDA receptors (background noise o Under these pathological conditions memantine binds on NMDA and prevents influx of Ca2+ o Protects against excitotoxicity and background noise As it is moderate in affinity, when a signal of sufficient strength comes it will dislodge and allow Ca2+ entry

Serotonin Involved in anxiety 5HT reduction is responsible for violent behaviour/impulsive behaviour Thus use of Citalopram to increase serotonin via inhibition of 5HT reuptake is used to treat behavioural changes!

Disease Slowing / Modification APP metabolism Ab deposition Phosphorylation of Tau

Issues with disease modifying treatments: Animal modelss construct validity is not perfect Predictive value not established yet Anti-amyloid therapies BACE inhibitors Gamma secretase inhibitors MAOB inhibitors Ab vaccination Memantine GGSK inactivation BACE inhibitors (beta secretase) reduces Ab aggregation Gamma-secretase inhibitors reduce Ab aggregation Amyloid beta vaccination reduces pathology in mice (PDAPP) o o o Stopped at phase II due to development of meningoencephalitis Worked by attaching to plasma Ab, via m266 antibody which prevents re-entry into CSF Also possible microglial clearance via phagocytosis or reactive metabolism

MAOB inhibitors SELEGILINE Vit E Acts as antioxidant as MAO produces ROS Increased active life span of animals Increases catecholamines = increase in cognition! Reduced cell death via antioxidant post cerebral ischemia Reduced lipid peroxidation Reduced Ab associated cell death!

Tau Tangle Therapy When Tau is phosphorylated via GSK3b, it causes paired helical filaments Hyperphosphorylation of tau protein can result in self-assembly into tangles of paired helical filaments with straight filaments creating tangles! Formation of tangles in nerve cell body causes microtubules to disintegrate, promoting cell death!

Memantine inactivates GSK3b by facilitating GSK3b serine phosphorylation to inactivate it!

Stroke
Ischemic Brain atery blocked Embolic stroke (clot forms outside brain artery) Thrombotic clot (formation of clot within brain artery) Haemorrhagic Brain artery bursts Intracerebral - blood enters into substance of brain Subarachnoid blood enters various spaces surrounding the brain Risk factors Diabetes Obesity Coronary heart disease Congenital heart defects Heavy alcohol use Cocaine Symptoms Numbness Weakness Inability to move face or arm on one side Vision distortion (blindness in one eye or blurred double vision) Confusion and difficulty understanding Speech problems Balance Headache Neuropathology Ischemic Core cells die immediately (minutes/hours) Penumbra surrounding tissue, blood supply compromised but not cut off, can be reperfused! (cells under threat) Mechanisms contributing to cell death in stroke Core excitotoxicity Penumbra Excitotoxicity, Necrosis, Ox stress, inflammation, apoptosis

**reperfusion resuklts in massive release of proinflammatory mediators and results in toxicity via inflammation and oxidative stress! Glial activation Oedema MHC expression Systemic acute phase response with general inflammation and acute phase protein synthesis Complement activation e.g. anaphylatoxins, membrane attack complex Synthesis of inflammatory mediators e.g. cytokines, free radicals, prostaglandins Expression of adhesion molecules Invasion of immune cells