BS1060 - CNS 3 - 2025

Overview of the central nervous system (CNS) and its importance in biological sciences.
Topics of discussion:
- Cross-species comparison of brain structures.
- Special characteristics of the human brain.
- The influence of aging and the development of dementia.

Other distinctions:
- Larger than expected for an ape.
- Neocortex approximately three times larger than expected for body size.
- Specific areas of the neocortex and cerebellum larger than predicted.
- More white matter than other primates.
Overall, the human brain can be seen as a scaled-up version of a primate brain, structurally similar but with more neurons.

Aspect	Generic Rodent Brain	Generic Primate Brain	Human Brain
Brain mass (g)	1500	1500	1508
Total number of neurons	12 billion	93 billion	86 billion
Total number of non-neurons	46 billion	112 billion	85 billion
Mass, cerebral cortex (g)	1154	1412	1233
Neurons, cerebral cortex	2 billion	25 billion	16 billion
Relative size of cerebral cortex	77%	94%	82%
Neurons in cerebellum	10 billion	61 billion	69 billion

Healthy age-related cognitive decline typically begins in the 60s, but varies per individual.
Alzheimer’s Disease (AD) changes detectable decades before symptoms appear.
Stages of cognitive decline:
- Amnestic Mild Cognitive Impairment (MCI): Memory problems with other cognitive functions intact.
- Cognitive decline accelerates post-AD diagnosis.
- Life course projection from birth to death highlighting cognitive health.

Current statistics:
- Around 850,000 people in the UK are living with dementia.
- Projections:
  - Over one million by 2025.
  - Exceeding 2 million by 2050.
Financial implications of dementia on society:
- Costs to the state for social care: £4.5 billion.
- Unpaid care: £11.6 billion.
- Health care: £4.3 billion.
- Individual social care: £5.8 billion.
- Additional miscellaneous costs: £100 million.

Healthy aging is characterized by moderate neuronal cell loss, yet decreases in neuron complexity and synaptic connections.
Resultant shrinkage of the cerebral cortex is observed.

Alzheimer’s Disease (AD) is the most frequent form of dementia, accounting for 60-80% of cases.
Initially detailed by Alois Alzheimer in 1906.
Characteristics:
- Gradual onset, progressively worsening neurodegenerative disease.
- Symptoms include memory loss, language difficulties, disorientation, and behavioral changes.
Pathological changes encompass:
- Severe neuronal cell loss.
- Formation of amyloid plaques.
- Neurofibrillary tangles due to tau protein accumulation.

Composed primarily of beta-amyloid (Aβ) and located between neurons.
Neurofibrillary Tangles: Composed of tau protein found inside neurons.
Progression of amyloid plaques from the neocortex to deeper brain structures.
Tau tangles start at locus coeruleus and spread through regions including the entorhinal cortex and hippocampus.

Tau is crucial for stabilizing the microtubule network (cytoskeleton) in mature neurons.
Normally phosphorylated; however, in AD, tau is hyperphosphorylated (3 to 4-fold increase).
Other tauopathies linked to tau hyperphosphorylation include fronto-temporal dementia and Pick disease.

APP is a class 1 transmembrane protein involved in:
- Synapse formation and repair.
- Anterograde neuronal transport.
- Iron export.
Processing pathways:
- Non-amyloidgenic pathway: α-secretase.
- Amyloidgenic pathways: β- and γ-secretases resulting in Aβ monomer formation (37-49 amino acids long).

Aβ oligomers or prefibrillar structures are the most neurotoxic, causing damaging interactions with multiple receptors leading to:
- Excess calcium influx.
- Tau hyperphosphorylation.
- Generation of free radicals.
- Chronic microglial activation leading to inflammation.

Traditional Drug Approvals: 5 approved drugs for AD symptoms:
- Donepezil, galantamine, rivastigmine (acetylcholine esterase inhibitors).
- Memantine (NMDA-receptor channel blocker).
- Namzaric (combination of memantine + donepezil).
Potential treatment targets include:
- Amyloid plaques and tau tangles.
- Immunotherapy; Aβ-degrading proteases.
- Inhibitors for β- and γ-secretases, tau phosphorylation, and aggregation.

Over 100 drugs currently being developed, promising candidates include:
- Donanemab (data released).
- Lecanemab (FDA approved in the US).
- Remternetug (ongoing clinical trials).
- All are immunotherapy drugs focused on clearing amyloid plaques.

Successful treatment developments hinge on discovering better and earlier biomarkers for disease-modifying therapies in preclinical stages.
Leading candidate biomarkers involve:
- CSF levels (tau and Aβ42 levels).
- PET tracers for amyloid plaques imaging.

The human brain does not exhibit definitive features distinguishing it from other primate brains.
Unlike healthy aging, dementia typically results in progressive neuron loss.
Alzheimer’s Disease remains the most prevalent dementia form, marked by the development of amyloid plaques and neurofibrillary tangles.
Current treatments address symptoms rather than the underlying causes of Alzheimer’s Disease.