Pathogenesis of Alzheimer's disease : focus on amyloid β-peptide, homocysteine and metals

Alzheimer's disease (AD) is a complex dementia disorder. It is characterized by the neuronal and synaptic loss, presence of neurofibrillary tangles and senile plaques, composed of amyloid β-peptide (Aβ) in the brain. Biochemical and genetic studies implicate a central role for Aβ in the pathogenesis of AD, however how amyloid leads to neurodegeneration is still unknown. The present work focused on investigating the role of Aβ in AD and other relevant neurological and psychiatric disorders. The study was based on the analysis of Aβ in cell culture media and post-mortem brain tissue.

In paper I, we measured Aβ in cell culture media from cells transfected with APP mutations causing familial AD. We could see that mutations in familial AD are primarily pathogenic through their effect on APP processing and not through altered cell signaling. In paper II, we compared the levels of Aβ in the brain of elderly schizophrenics with and without dementia versus controls. We demonstrated that in the brains from people with schizophrenia and dementia there is no increase of Aβ. Thus the pathogenic pathway of dementia in elderly schizophrenics is different from that seen in AD.

Additionally, in schizophrenia cases with AD neuropathology, levels of brain Aβ were decreased as compared to 'pure' AD cases. This may be explained by high smoking prevalence among schizophrenics, the use of neuroleptic drugs or could be a result of the disease state per se. In paper III, we further investigated the hypothesis that stimulation of nicotinic receptors may diminish amyloidosis in the brain. We could prove that deposition of Aβ is attenuated in the cortex of normal elderly people that used to smoke tobacco. However, the mechanism of this attenuation is unknown.

Metals have been implicated in AD pathogenesis and some metal chelators have shown therapeutic promise in animal and human studies. In paper IV, we studied the interaction of human brain Aβ with biometals, such as zinc, copper, aluminium, iron and manganese. We extracted and measured cortical Aβ in AD patients and control groups. The levels of the metals were assessed in a parallel set of samples. We found that zinc is strongly elevated in AD brains and is correlated with Aβ and dementia severity.

In paper V, we focused on other important factors in AD pathogenesis, such as homocysteine and vitamin B status. We compared plasma homocysteine levels in controls, AD patients and in patients with mild cognitive impairment. We observed hyperhomocysteinemia in AD. We also confirmed that ApoE 4 allele is a risk factor in the development of sporadic AD. We did not find any evidence that polymorphism of the enzyme involved in homocysteine biogenesis, methylenetetrahydrofolate reductase (MTHFR), has a clinical significance in these groups.

In summary, these studies suggest a multifactoral pathogenesis of AD, where Aβ, zinc and homocysteine are important factors. They also give insight into targets to develop therapeutic strategies for treatment of dementia. Those include: substances stimulating nicotinic receptors, metals chelators, anti- hyperhomocysteinemia therapies, and anti-Aβ strategies.

List of scientific papers

I. Bergman A, Religa D, Karlstrom H, Laudon H, Winblad B, Lannfelt L, Lundkvist J, Naslund J (2003). APP intracellular domain formation and unaltered signaling in the presence of familial Alzheimer's disease mutations. Exp Cell Res. 287(1): 1-9.
https://pubmed.ncbi.nlm.nih.gov/12799176

II. Religa D, Laudon H, Styczynska M, Winblad B, Naslund J, Haroutunian V (2003). Amyloid beta pathology in Alzheimer's disease and schizophrenia. Am J Psychiatry. 160(5): 867-72.
https://pubmed.ncbi.nlm.nih.gov/12727689

III. Court JA, Johnson M, Religa D, Keverne J, Kalaria R, Jaros E, McKeith IG, Perry R, Naslund J, Perry EK (2005). Attenuation of Abeta deposition in the entorhinal cortex of normal elderly individuals associated with tobacco smoking. Neuropathol Appl Neurobiol. 31(5): 522-35.
https://pubmed.ncbi.nlm.nih.gov/16150123

IV. Religa D, Strozyk D, Cherny RA, Volitakis I, Haroutunian V, Winblad B, Naslund J, Bush AI (2006). Elevated cortical zinc in Alzheimer disease. Neurology. 67(1): 69-75.
https://pubmed.ncbi.nlm.nih.gov/16832080

V. Religa D, Styczynska M, Peplonska B, Gabryelewicz T, Pfeffer A, Chodakowska M, Luczywek E, Wasiak B, Stepien K, Golebiowski M, Winblad B, Barcikowska M (2003). Homocysteine, apolipoproteine E and methylenetetrahydrofolate reductase in Alzheimer's disease and mild cognitive impairment. Dement Geriatr Cogn Disord. 16(2): 64-70.
https://pubmed.ncbi.nlm.nih.gov/12784029